Ebola immunosupression and infection

Ebola immunosupression and infection

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I was wondering… If Ebola attacks immune cells and causes immunosupression, then shouldn't we see death in Ebola patients due to secondary infection?

Yes, we should. But Ebola doesn't completely immunosuppress us, or there would be no survivors.

Ebola kills by overwhelming the body before enough antibodies are formed to fight it.

If you're one of the survivors (as about 40-50% are, more with good care), you'll have antibodies to Ebola in your blood which might help someone else infected with Ebola.

If you're not one of the survivors, it's still likely you'll have some antibodies, but the shock your body goes into from all the dead cell products in your blood (which - overly simplified - causes a cytokine storm -> leaky capillaries -> fluid balance problems -> end organ failure -> death).

Signs and Symptoms

Symptoms may appear anywhere from 2 to 21 days after contact with the virus, with an average of 8 to 10 days. The course of the illness typically progresses from &ldquodry&rdquo symptoms initially (such as fever, aches and pains, and fatigue), and then progresses to &ldquowet&rdquo symptoms (such as diarrhea and vomiting) as the person becomes sicker.

Primary signs and symptoms of Ebola often include some or several of the following:

  • Fever
  • Aches and pains, such as severe headache and muscle and joint pain
  • Weakness and fatigue
  • Sore throat
  • Loss of appetite
  • Gastrointestinal symptoms including abdominal pain, diarrhea, and vomiting
  • Unexplained hemorrhaging, bleeding or bruising

Other symptoms may include red eyes, skin rash, and hiccups (late-stage).

Many common illnesses can have the same symptoms as EVD, including influenza (flu), malaria, or typhoid fever.

EVD is a rare but severe and often deadly disease. Recovery from EVD depends on good supportive clinical care and the patient&rsquos immune response. Studies show that survivors of Ebola virus infection have antibodies (proteins made by the immune system that identify and neutralize invading viruses) that can be detected in the blood up to 10 years after recovery. Survivors are thought to have some protective immunity to the type of Ebola that sickened them.

Citation: Younan P, Iampietro M, Bukreyev A (2018) Disabling of lymphocyte immune response by Ebola virus. PLoS Pathog 14(4): e1006932.

Editor: Rebecca Ellis Dutch, University of Kentucky, UNITED STATES

Published: April 12, 2018

Copyright: © 2018 Younan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This study was supported by the NIH grant U19 AI109945-01 Project 2 Molecular Basis for Ebola Virus Immune Paralysis (AB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Studying Ebola Survivors

Amanda B. Keener
Apr 6, 2015

Emory University Hospital WIKIMEDIA, DANIEL MAYER On a cloudy afternoon in March, immunologist Rafi Ahmed is at work in the basement of the Rollins Research Center at Emory University in Atlanta, just down the street from the US Centers for Disease Control and Prevention (CDC). Months earlier, Ahmed had begun studying immune cells in blood collected from four Ebola survivors treated in Emory University Hospital&rsquos Serious Communicable Diseases Unit last year. He and his colleagues last month (March 9) detailed in PNAS a robust immune response driven by the Ebola virus during and after infection. &ldquoIt&rsquos truly the first look at what&rsquos happening to B and T cell responses during the acute phase of infection,&rdquo Ahmed told The Scientist.

&ldquoAnything we learn about pathogenesis is very important,&rdquo said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID) who was not involved in the work.

When Ahmed first heard that Ebola patients would be treated at Emory last fall, he immediately contacted the clinical team and the CDC to get patient consent and access to some of the samples. “They were going to do the viral load anyway, so I said let’s do some immunology at the same time,” he said.

While news of the first Ebola patients arriving in the U.S. stirred public alarm, the postdocs in Ahmed’s lab were mobilized into action, working closely with Anita McElroy, an infectious disease specialist with dual appointments at Emory and the CDC. “They were working ’round the clock when the patients were there,” said Ahmed. The sense of urgency continued to build as more patients were admitted to Emory in the following months.

Only McElroy could handle the viremic blood in a biosafety level 4 (BSL-4) unit at the CDC, so members of Ahmed’s lab waited anxiously to analyze each piece of raw data as soon as they were granted access to it. The equipment available in the BSL-4 lab limited the team to measuring just four cellular parameters at a time, but that was enough to make some surprising observations. The Ebola patients’ blood contained unexpectedly large populations of activated adaptive immune cells called B cells and T cells.

“The conventional wisdom is that Ebola is highly immunosuppressive,” said Ahmed. “One of the reasons you have these high levels of viremia is that the immune system can’t kick in.”

But in these four patients, the immune system was kicking in, and in a big way. The most prominent population was the CD8+ T cells, which are known for killing virally infected cells. The researchers also incubated CD8+ T cells with different Ebola proteins and found that the cells responded most strongly to a protein called NP, which Ahmed pointed out is not included in either of the Ebola vaccines currently in human trials.

Nancy Sullivan, chief of biodefense research in at the NIAID, who helped develop one of these vaccines, said she was not surprised that NP generated such a strong response, since it is one of the first proteins made by Ebola during infection, and therefore one of the most abundant. Sullivan said this may also be why a study of blood samples collected during a 1996 Ebola outbreak in Gabon found that survivors tended to make more antibodies against NP than did people who died of the disease. Sullivan noted that vaccination with the Ebola glycoprotein (GP) was enough to protect nonhuman primates from the virus and, in some cases, adding NP to the GP vaccine hindered its effectiveness.

While NP may play a role in natural infection, Sullivan’s team opted to go forward with just GP the group has shown that its vaccine candidate can induce antibodies and CD8+ T cell responses in humans. Ahmed’s team is interested in comparing the responses generated by vaccines to those induced by natural infection, but he cautioned that his group’s data can’t define which aspects of the immune response may have been responsible for the Emory patients’ recoveries.

The four survivors have agreed to donate blood every six months for three years, so that Ahmed and other researchers can track immunity against the virus over time. This team recently secured a grant from the Defense Advanced Research Projects Agency (DARPA) to do a variety of follow-up studies using convalescent samples, which can be safely handled outside the CDC. Ahmed’s immediate goal is to use the information gathered so far to generate Ebola-neutralizing monoclonal antibodies for therapeutic use. His group will sequence the genes that code for antibodies made in response to GP used them to produce large quantities of the best antibody candidates. A member of the DARPA coalition will then test the candidates in animal models.

Other researchers will use these samples to define the receptors used by B and T cells to detect Ebola and track how immune memory cells are formed. They will also look for epitopes on Ebola proteins that are most likely to activate those memory cells. Though this work could help improve future vaccine designs, much of it will ask basic research questions that have been impossible to explore until now. “This outbreak, as terrible as it is, in the long run will help us understand how the disease progresses in humans,” said Sullivan.

Ebola Virus Disables the Body's Immune Defenses

New study has uncovered how Ebola virus can exert such catastrophic effects on the infected person. The study was conducted by researchers from The University of Texas Medical Branch at Galveston.

They've described for the first time how the virus disables T cells, an important line of immune defense, thus rendering the infected person less able to combat the infection. The findings are currently available in PLOS Pathogens.

Ebola virus disease is one of the most devastating infectious diseases known to exist, with previous outbreaks resulting in high fatality rates.

White blood cells are an important part of our immune system. Lymphopenia happens when the white blood T cell count in the bloodstream is lower than normal - in fact, the extent of lymphopenia is one of the strongest indicators of how severe the Ebola infection will become.

"People who survive an Ebola infection are able to maintain their T cell levels over the course of the infection whereas low T cell levels are nearly universally seen in fatalities," said senior author Alex Bukreyev, a UTMB virologist in the departments of pathology and microbiology and immunology. "The trouble is that we've never understood how this T cell depletion occurs, so we set out to answer this question."

Using cellular biology and genetic approaches, the researchers demonstrated for the first time how the Ebola virus can attach to, enter and infect T cells and what happens afterward. Although the virus is confined within the infected T cells, they become stressed to the point where the body destroys them. This contributes to the lymphopenia that's linked to disease severity.

"With this new information, we're planning to investigate the role of these processes in Ebola-induced white blood cell death, immunosuppression and disease development in general," said Bukreyev.

Researchers uncover how Ebola virus disables immune response

Ebola virus virion. Credit: CDC

One of the human body's first responses to a viral infection is to make and release signaling proteins called interferons, which amplify the immune system response to viruses. Over time, many viruses have evolved to undermine interferon's immune-boosting signal, and a paper published today in the journal Cell Host & Microbe describes a mechanism unique to the Ebola virus that defeats attempts by interferon to block viral reproduction in infected cells.

The newly published study explains for the first time how the production by the virus of a protein called Ebola Viral Protein 24 (eVP24) stops the interferon-based signals from ramping up immune defenses. With the body's first response disabled, the virus is free to mass produce itself and trigger the too-large immune response that damages organs and often becomes deadly as part of Ebola virus disease (EVD).

The study was led by scientists from Washington University School of Medicine in St. Louis in collaboration with researchers from the Icahn School of Medicine at Mount Sinai and the University of Texas Southwestern Medical Center.

"Our study is the first to show how Ebola viral protein 24 defeats the signal sent by interferons, the key signaling molecules in the body's early response to Ebola virus infection," said Christopher F. Basler, PhD, Professor of Microbiology at the Icahn School of Medicine at Mount Sinai, and an author of the newly published paper. "These newfound details of Ebola biology are already serving as the foundation of a new drug development effort, albeit in its earliest stages," said Dr. Basler, also a researcher within the Mount Sinai Global Health and Emerging Pathogens Institute.

"We've known for a long time that infection with Ebola virus obstructs an important arm in our immune system that is activated by molecules called interferons," said senior author Gaya Amarasinghe, PhD, Assistant Professor of Pathology and Immunology at Washington University School of Medicine in St. Louis. "By determining the structure of an eVP24 in complex with a cellular transporter, we learned how Ebola does this."

Ebola Defeats Immune Defenses Early in Infection

The study spotlights the part of the body's defense system that fights infection called innate immunity, the mix of proteins and cells that most quickly recognizes an invasion by a virus. This part of immunity keeps a virus from quickly reproducing inside cells.

To trigger an effective, early response to viral infection, interferons must pass on their signal to other cells. This occurs through other messengers inside cells as part of interferon signaling pathways, with the last of these messengers turning on genes inside the nuclei of cells to drive the immune response.

The current study determined the structure of eVP24 when bound to its cellular targets, transport proteins called karyopherins. The study used these structures to show how, in place of interferon's natural downstream signal carrier phosphorylated STAT1, eVP24 docks into the karyopherins meant to escort STAT1 into cell nuclei where it turns on interferon-targeted genes. By elegantly interfering at this stage, eVP24 cripples innate immunity to cause EVD.

In 2006, Dr. Basler and colleagues found that the Ebola virus suppresses the human immune response through eVP24, but not how. Through of combination of molecular biology techniques, cell studies and tests that reveal protein structures, the current team led by Dr. Amarasighe defined the molecular basis for how eVP24 achieves this suppression.

Understanding exactly how the Ebola virus targets the interferon pathway could help guide drug development moving forward. Dr. Basler describes how it may be possible to find an antibody or molecule that interferes with eVP24, or that works around its competition with STAT1, such that treatment of patients with extra interferon, long used against the hepatitis C virus for instance, might become useful against the Ebola virus.

"We feel the urgency of the present situation, but still must do the careful research to ensure that any early drug candidates against the Ebola virus are proven to be safe, effective and ready for use in future outbreaks," said Dr. Basler, who is also principal Investigator of an NIH-funded Center of Excellence for Translational Research (CETR) focused on developing drugs to treat Ebola virus infections.

Ebola immunosupression and infection - Biology

An association between malaria and risk for death among patients with Ebola virus disease has suggested within-host interactions between Plasmodium falciparum parasites and Ebola virus. To determine whether such an interaction might also influence the probability of acquiring either infection, we used a large snapshot surveillance study from rural Gabon to test if past exposure to Ebola virus is associated with current infection with Plasmodium spp. during nonepidemic conditions. We found a strong positive association, on population and individual levels, between seropositivity for antibodies against Ebola virus and the presence of Plasmodium parasites in the blood. According to a multiple regression model accounting for other key variables, antibodies against Ebola virus emerged as the strongest individual-level risk factor for acquiring malaria. Our results suggest that within-host interactions between malaria parasites and Ebola virus may underlie epidemiologic associations.

Major outbreaks of infections with Ebola virus, such as the 2014–2016 West Africa epidemic and the ongoing 2018–2019 outbreak in eastern Democratic Republic of the Congo, pose several obvious and immediate threats to public health. Less obvious, but as concerning for public health, is the possibility that Ebola virus might also interact with common cocirculating infectious agents at both the population and within-host (individual) levels. Indeed, much attention has been paid to the relationship between malaria and Ebola virus disease (EVD), primarily because of the clinical resemblance between the 2 diseases (1) and the high frequency of Plasmodium spp. co-infection among patients undergoing treatment for confirmed EVD (2). At the individual level, several retrospective epidemiology studies of patients undergoing treatment for confirmed EVD have attempted to determine whether concurrent malaria affects patient outcomes. In Sierra Leone (3) and at 1 Ebola treatment center in Liberia (4), mortality risk was much higher among Ebola patients who were co-infected with Plasmodium parasites than among patients who were not co-infected, and a study in Guinea found that adverse outcomes were higher among EVD patients with higher P. falciparum parasite loads than among those with lower levels of parasitemia (5). A similar study of patients at several Ebola treatment centers in Liberia reported the opposite relationship, that the probability of survival for EVD patients was positively associated with both presence and level of Plasmodium spp. parasitemia (6). Together, these results point to a strong potential for biological interactions between Plasmodium parasites and Ebola virus that may influence the severity of EVD.

At the population level, interruption of normal public health services and disease control measures—including patient avoidance of healthcare facilities—during an EVD epidemic has been projected to cause increases in untreated cases and deaths from malaria, in addition to several otherwise preventable or treatable diseases (79). Yet whether biological interactions at the within-host level, such as inflammatory processes leading to prolonged post-Ebola syndrome symptoms common in acute EVD survivors (10), may also lead to a change in malaria transmission dynamics by influencing susceptibility remains unknown.

Knowledge of the extent of possible interactions between infection with Plasmodium parasites and Ebola virus is especially helpful because geographic regions where prevalence of antibodies against Ebola virus (hereafter called Ebola antibodies) is high are also areas of high malaria endemicity (11), particularly the most severe form of malaria, caused by P. falciparum (12). Historically, small, typically rural, outbreaks of Ebola virus have been the norm many such outbreaks across central Africa have been described since 1976 (13). However, the recent occurrence of large outbreaks involving multiple urban centers (14,15), including thousands of survivors and vaccinated persons, means that any interactions with malaria parasites have the potential to affect larger populations than in prior decades. Furthermore, it is estimated that less than half of the cross-species transmission events leading to a human EVD case are correctly identified by current surveillance systems, suggesting that most of these events are treated locally as an unknown fever or malaria (16).

To investigate the potential epidemiologic links between Ebola virus exposure and malaria parasites, we took advantage of a large snapshot surveillance study of 4,272 adults from 210 villages across Gabon, conducted during 2005–2008 (1719), to test for populationwide and individual associations between the 2 infections during nonepidemic conditions. At both levels, we also tested for key cofactors that might influence detection of an association. With an Ebola antibody seroprevalence of 15.3% (17,18) and Plasmodium spp. prevalence of 52.1% (19), our study population offered the unique opportunity for testing such a link.

Materials and Methods

Study Population and Survey Methods

Our study was based on data previously generated from a snapshot surveillance study in rural Gabon (1721). That study was conducted across 210 rural (population <300) villages in Gabon, located across a variety of open and forested habitats, and was designed specifically to test for the prevalence of undetected exposure to Ebola virus (17,18). Villages were selected by using a stratified random sampling method based on Gabon’s 9 administrative provinces each province was surveyed once during 1-month field missions from July 2005 through May 2008, generally during the dry season. All but 5 of Gabon’s 49 administrative departments (grouping villages within provinces) were represented (Appendix Figure 1). In each village, all permanent residents >15 years of age were solicited for participation in the study if they were willing to complete a 2-page survey and provide a blood sample along with written consent. The survey included questions about sociodemographics and medical history. All participants and nonparticipants in each village were offered information about the study, free medical examinations, malaria testing, blood typing, and medicines. Refusal to participate was low (≈15% of eligible persons). The study protocol was approved by the Gabonese Ministry of Health (research organization no. 00093/MSP/SG/SGAQM) and is described elsewhere (1720).

Individual Pathogen Exposure and Cofactors

Study volunteers were tested for previous exposure to Ebola virus by use of a Zaire ebolavirus (ZEBOV) IgG–specific ELISA (17,18). Current infection with Plasmodium spp. was tested by using an in-field blood smear (17,18) and by high-throughput targeted sequencing of Plasmodium-specific cytochrome b mitochondrial DNA to identify species (single and mixed infections of P. falciparum, P. malariae, and P. ovale were identified) (19). For purposes of this study, we considered a person to be infected with malaria parasites if either blood smear or sequence amplification was positive (irrespective of the species) and to not be infected if both test results were negative.

In addition to participant sex and age group (16–30, 31–45, 46–60, >60 years), information was obtained about several cofactors that could be indicative of heterogeneous exposure or susceptibility to both infections (17,18). These cofactors included the presence of concurrent filarial worm infection (Loa loa and Mansonella perstans, each identified from blood samples as described in [20]), sickle cell hemoglobin genotype (carriers vs. noncarriers, as determined in [21]), participant education level (classified as less than secondary education or secondary education and above, serving as a proxy for socioeconomic status), participant regular contact with wild animals through primary occupation (classified as hunters or nonhunters), the keeping of wild animals as pets (yes or no), and specific exposure to bats by consumption (yes or no).

Population Cofactors

For determination of population-level influences on patterns of pathogen exposure, factors common to all persons in a given department or village were also examined. We obtained population density (no. persons/km 2 ) at the department level by dividing population size (no. inhabitants/department based on 2003 national census data, by department area (km 2 ). Average household wealth and frequency of insecticide-treated mosquito net (ITN) ownership per department were obtained from the Demographic and Health Surveys program 2012 survey for Gabon (22). Geographic displacement of households in these data remained within administrative boundaries however, wealth and ITN data were missing for 7 departments (Appendix Table 1). Average household wealth was calculated by rescaling the wealth index for all rural households to positive integers and taking the geometric mean for each department. We calculated the frequency of ITN ownership per department by counting the number of rural households in each department with at least 1 ITN and dividing it by the number of households for which there were data. At the village level, the dominant habitat type was previously classified into 3 categories with statistically significant differences in terms of Ebola antibody prevalence: lakeland (including lakes, rivers and coastal regions), savanna (including savanna and grassland areas), and forest (including northeastern forests, interior forests, and mountain forest areas) (17,18).

Statistical Analyses

We performed all statistical analyses in the R version 3.2.2 statistical programming environment (23). We tested for departure of malaria and Ebola antibody co-occurrence frequency from random expectations by using χ 2 analysis (chisq.test function in R). We tested the correlation between department-level prevalence of Ebola antibodies and malaria parasite infection by using the cor.test function in R, based on the nonparametric Spearman rank correlation coefficient. We tested department-level effects of population density, average wealth, and ITN ownership frequency on this correlation together as cofactors in a mixed-effects multiple linear regression model (function lmer, package lme4) by setting Ebola antibody prevalence as the main explanatory variable, Plasmodium spp. prevalence as the response variable, and province as a random variable to limit pseudoreplication. The inclusion of province as a random variable also enabled us to account for yearly and seasonal differences in prevalence because all departments within a given province were sampled within a single month-long field mission. To meet assumptions of normality, antibody prevalence, Plasmodium parasite prevalence, and ITN ownership frequency were arcsine square-root transformed, population density and average wealth were log-transformed, and data points were weighted by the number of persons tested in each department. Data for the 7 departments with missing wealth and ITN data were excluded from the multiple regression model.

At the individual level, we used multiple logistic regression (implemented as a generalized linear mixed effects model with binomial error distribution via the glmer function of package lme4) to test whether persons with Ebola antibodies were more or less likely than those without Ebola antibodies to also be infected with malaria parasites. Plasmodium parasite infection status (infected or not infected) was the response variable in the model, and we included province (also accounting for date sampled), department within province, and village (nested within department and province) of the person as random factors to control for pseudoreplication and spatial autocorrelation. Explanatory variables included ZEBOV-specific IgG seropositivity, individual cofactors (concurrent L. loa and M. perstans infection sex age group sickle cell genotype education level and regular interaction with animals through hunting, keeping wild pets, or consuming bats), and population-level cofactors (village habitat and log-transformed population density of the administrative department). We tested the effect of each explanatory variable after correcting for all other model terms via likelihood ratio tests, reported as adjusted odds ratios, and used bootstrapping to calculate the 95% CIs of the coefficients by using the bootMer function (R boot package, no. Markov chain Monte Carlo simulations = 200). We removed from analysis those persons for whom values for any 1 variable were missing.


Figure 1. Frequency of Plasmodium spp. infection and Zaire ebolavirus–specific IgG seropositivity among participants in study of exposure to Ebola virus and risk for malaria, rural Gabon. +, positive.

A total of 4,272 volunteers from 210 villages were enrolled in the study. Among those sampled, we obtained data on both malaria status and Ebola antibodies from 4,170 persons: 2,199 (52.7%) female and 1,971 (47.8%) male participants, 16–90 (median 49) years of age. These data showed that across Gabon, 2,190 (52.5%) persons were infected with > 1 species of Plasmodium, 638 (15.3%) were positive for ZEBOV-specific IgG, and an overabundance of 425 (10.2%) were in both categories (Figure 1 χ2 = 59.4, df = 1, p<0.0001). Because of missing data, we analyzed individual-level risk factors for exposure to both pathogens on a subset of 3,912 persons (Table Appendix Table 1).

Figure 2. Association of Ebola virus exposure and Plasmodium spp. infection across rural communities in Gabon. A) Geographic distribution of Ebola virus antibody seroprevalence. B) Geographic distribution of malaria parasite (all Plasmodium species).

At the population level, we found a striking positive correlation between the geographic distributions of Ebola virus exposure and Plasmodium parasite infection, measured as the prevalence of each across administrative departments (Figure 2 Spearman rank correlation coefficient ρ = 0.43, df = 42, p<0.01). The direction and significance of this correlation was not qualitatively affected by population density, average household wealth, ITN ownership frequency, or by controlling for random variance among provinces sampled on different dates (Appendix Table 2, Figures 2, 3).

Figure 3. Malaria parasite infection risk factor effect sizes. The relationship between malaria and each individual or population-level risk factor was evaluated after accounting for all other variables, including geographic location (village within.

At the individual level, we found that prior exposure to Ebola virus was strongly associated with an increased probability of current Plasmodium spp. infection, even after accounting for geographic location (administrative province, department, and village) and all other individual and population-level risk factors in the model (adjusted odds ratio [aOR] 1.741 [95% CI 1.400–2.143], χ 2 = 26.36, df = 1, p<0.0001 Figure 3 Appendix Table 3, Figure 4). This variable was a stronger risk factor for Plasmodium infection than any other individual trait, second only to living in a lakeland habitat (aOR 0.313 [95% CI 0.110–0.875], χ 2 = 11.64, df = 2, p<0.01) (Figure 3 Appendix Table 3). Other factors positively associated with Plasmodium parasite infection were concurrent infection with M. perstans (aOR 1.359 [1.056–1.727], χ 2 = 5.35, df = 1, p = 0.021), male sex (aOR 1.335 [1.098–1.586], χ 2 = 10.5, df = 1, p = 0.0012), and keeping a wild animal as a pet (aOR 1.308 [1.040–1.654], χ 2 = 4.55, df = 1, p = 0.033). Being in an older age group was associated with a decline in Plasmodium parasite infection risk (χ 2 = 8.02, df = 1, p = 0.046). From the individual-level model we excluded department-level wealth and ITN ownership frequency, which showed no evidence for influencing the association at the population level (Appendix Table 2) because these variables were confounded with department-level population density and because missing data were not randomly distributed (Appendix Table 1). These results for nonspecific malaria parasite infection risk factors were qualitatively identical when P. falciparum and P. malariae infections were considered separately (P. ovale infection was too rare to be tested Appendix Tables 4, 5).


At the population and individual levels across Gabon, we found a strong positive association between ZEBOV-specific IgG seropositivity and current malaria parasite infection. In geographic regions where Ebola virus exposure was high, prevalence of Plasmodium spp. infection was also high, and within these regions, having antibodies against Ebola virus increased the risk for current Plasmodium infection by nearly 75% after all other medical, demographic, social, behavioral, and ecologic cofactors for which we had data were controlled for. The magnitude of the association, particularly when compared with other risk factors (filarial worm infections, sex, age group, contact with wild animals, and village habitat type), was highly unexpected. This epidemiologic link between Ebola virus exposure and malaria is consistent with reports of high co-infection frequency during the 2014–2016 outbreak of EVD in West Africa (2) and suggests that ecologic processes between the 2 pathogens potentially influencing patient survival (3,4) may also influence susceptibility or transmission.

The public health implications of our findings are numerous. First, if Ebola virus infection renders patients and survivors more susceptible to malaria, healthcare providers should anticipate the need for additional malaria treatment and control measures after Ebola virus outbreaks beyond the increase predicted from disruption of healthcare services and reduced treatment-seeking behavior, which often accompany an outbreak. Second, if sublethal Ebola virus infections commonly co-occur with malaria, they may be missed because disease surveillance systems do not regularly screen for other causes of disease in Plasmodium-positive patients whose symptoms are consistent with malaria and resolve with malaria treatment. However, a trial in Liberia showed that antimalarial drugs inhibit Ebola virus infection of cells in culture (2426) and were associated with increased survival of EVD patients (4). This finding suggests that if active treatment for malaria helps modulate EVD severity, it may also result in Ebola virus infection frequencies being underestimated during epidemic and nonepidemic periods. Third, if the causal direction of the interaction is such that malaria increases susceptibility to Ebola virus, achieving malaria elimination goals across West and Central Africa may help prevent future EVD outbreaks. Indeed, our choice to consider past exposure to Ebola virus as an explanatory variable for current malaria parasite infection in our analysis was arbitrary, and additional analyses confirmed that reversing the positions of the 2 pathogens in the model did not qualitatively change the observed association pattern (Appendix Table 6, Figures 5, 6). Furthermore, a biological mechanism of interaction between the 2 pathogens with the potential to cause the association found here (such as persistent inflammatory processes in EVD survivors [10,27,28] or damage to specific tissues targeted by both pathogens [29,30]) remains to be elucidated. We do, however, point out that the mechanism is not likely to be general or the result of immunosuppression (e.g., because of AIDS) because neither of the 2 common filarial infections included as co-factors (L. loa and M. perstans) were risk factors for infection with Plasmodium parasites (Figure 3) and Ebola virus exposure (Appendix Figure 5). Last, the World Health Organization has noted that the most recent EVD outbreak in the Nord Kivu Province of the Democratic Republic of the Congo coincided with a surge in malaria cases in the region (31). Even if the interaction is not biological and a common ecologic, epidemiologic, or even sociological factor not tested here is responsible for driving an increase in the probability of exposure to both pathogens, further study to identify that factor could prove helpful for predicting and preventing future EVD outbreaks.

One key challenge to understanding the drivers of the patterns we report in this study is determining what ZEBOV-specific IgG seropositivity means. Ebola virus–specific IgG is known to persist for at least a decade after acute disease (32). However, it is not entirely clear whether the surprisingly high seroprevalence of Ebola antibodies found in population studies such as ours during nonepidemic periods (17,18,3336) are the result of undetected outbreaks, subclinical exposure to Ebola virus, or cross-reactivity with other unknown filoviruses. A recent modeling study estimated that nearly 75% of cross-species transmission events leading to a singular or small cluster of EVD cases go undetected (16), although widespread failure to detect acute EVD cases seems unlikely. Alternatively, evidence of subclinical antigenic stimulation has been documented, for example, by a survey of Ebola virus–specific IgG seroprevalence among domestic dogs. Frequency of Ebola virus–specific IgG was highest in dogs nearest to an outbreak epicenter in Gabon (37). Mild or asymptomatic Ebola virus infection is typically associated with low viral loads, limiting virus capacity for human-to-human transmission (3840). Thus, evidence suggests that widespread seroprevalence of Ebola antibodies outside of known epidemic periods could reflect past subclinical infection contracted through exposure to natural reservoirs (such as frugivorous bats [41,42]) however, studies of humans have yielded only minimal support for this hypothesis (40,43,44). Whereas asymptomatic seroconversion of household contacts of acutely ill patients and high-risk exposure (direct physical contact with blood or vomit) was demonstrated to occur at high frequency (11/24 persons) during the 1996 outbreak in Gabon (44), studies from the Democratic Republic of the Congo in 1995 (43) and during the 2014–2016 outbreak in Sierra Leone (40) found that this phenomenon was much more rare among household contacts with lower-risk exposure histories. Although these studies concluded that undiagnosed subclinical EVD and asymptomatic Ebola virus infections were evident during an outbreak, it has not yet been shown that they occur in the absence of diagnosed cases, let alone at sufficient frequency. Arguably, the most likely source of high Ebola antibody seroprevalence in the absence of large outbreaks is antibody cross-reactivity with an unknown and relatively asymptomatic virus however, whereas IgG is largely cross-reactive among Ebola virus species (45), no such low-virulence Ebola-related virus has been identified circulating in these populations. Irrespective of the processes that govern the presence of Ebola-specific antibodies, the strong and consistent associations we found between antibody status and Plasmodium parasite infection risk suggest a need for additional investigation regarding the effect of the source of these antibodies on malaria epidemiology and vice versa.

In addition to resolving uncertainty around the provenance of Ebola-specific antibodies in the absence of known cases, future studies should aim to ascertain more detailed information on the timing, duration, and severity of Plasmodium infections. In particular, it would be very informative to know whether the positive association detailed here is also found in children (our study excluded persons <16 years of age) because the prevalence of acquired immunity against many pathogens, including Ebola virus (17) and Plasmodium spp. (46), increases with age because of accumulating exposure opportunities. A longitudinal cohort (following infection and immunity status of each individual through time) would produce results with more reliable interpretation than the cross-sectional (single time-point snapshot) design of our present study (47). Ultimately, only case-controlled experimental studies, such as vaccine trials, can provide the evidence necessary to claim a causal relationship between these 2 pathogens in humans.

The 2014–2016 Ebola virus outbreak in West Africa served as a wake-up call, highlighting the possibility of Ebola virus emergence into new and heavily populated regions and spurring the advancement of vaccine development and case-reactive ring vaccination methods (48,49). However, with >17,000 EVD survivors across West Africa and an unknown number of asymptomatic seroconverted persons (50), it is important to clarify the mechanistic basis of our findings because this knowledge will help guide future investigations into public health implications, including the risk for acquiring malaria among EVD survivors and the potential for added benefits of both Ebola and malaria vaccination campaigns.

Dr. Abbate is a postdoctoral researcher at the French Institut de Recherche pour le Développement, where she has been investigating pathogen–pathogen associations from disease surveillance data by using empirical and theoretical tools. Her research interests include disease distributions, ecological interactions, host resistance evolution, and complex pathogen traits.

Why Is Covid-19 More Deadly Than Ebola? An Infectious Disease Doctor Explains

Medical workers transfer a deceased Covid-19 patient to a morgue in Brooklyn, New York.

In the pantheon of infectious disease killers, Ebola virus stands out as one of the deadliest. The Zaire species of Ebola kills somewhere between 40% to 90% of its victims, and usually upwards of 60% of infected people die. Only a handful of infectious diseases can claim such high death rates, including rabies, pneumonic plague, and inhalational anthrax.

The SARS-CoV-2 virus that causes Covid-19 illness surpassed a grim milestone in early July. The number of deaths from Covid-19 in Africa—more than 11,950—exceeded the total number of people who died during the largest-ever Ebola outbreak in West Africa, according to the World Health Organization.

How could this be? How could a disease that usually kills greater than 60% of its victims be outgunned by Covid-19, which “only” kills about approximately 4% of its victims, by the latest numbers.

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The answer relates to one fundamental aspect of most viruses. They don’t really like to kill their hosts. They can have a much wider impact if their hosts don’t die. This allows them to circulate in the community much longer and spread far and wide across the world for far greater impact.

When someone becomes ill with Ebola virus, they become bedridden very quickly. It’s really hard to be out in the community spreading disease if you are vomiting or having massive diarrhea. The people who are at greatest risk for Ebola infection are those who have very close contact taking care of the sick, bedridden victims—whether they are in the home or the hospital. Add to that, Ebola virus doesn’t spread until the victim has symptoms. This makes determining who is infected with Ebola and deciding who to isolate and quarantine much simpler than with Covid-19.

Liberian Red Cross team, in Monrovia, Liberia battling the worst-ever Ebola epidemic.

Marcus DiPaola/NurPhoto via Getty Images

Some infected people can spread Covid-19 without symptoms or before they have symptoms. Such individuals won’t be bedridden at the time they are contagious. Instead, they can hang out at a beach party or in a bar and be spreading the virus without even knowing they have been infected. The more contagious a human host is, and the more social interactions they have in the community, the more opportunities there are for a virus to spread during those interactions, and the more it will spread.

This is the bedrock behind the measures that public health authorities have been championing since the beginning of the Covid-19 pandemic: quarantine (restricted movement of those exposed, but not yet ill), isolation (restricted movement of those who are ill), masks (to reduce chance for spread, since we don’t know by looking at someone whether they are infected), and social distancing (to minimize close interactions between people).

Other countries have figured this out. Why hasn’t the United States?

Ultimately, though, a disease like Covid-19 that has a lower fatality rate, on average, in a single patient, can actually kill more people based on simple math. More people infected translates to more deaths. This is where Covid-19 wins hands down, and the reason that the recent surge in cases across parts of the United States is so dangerous. The more people are infected and contagious, the more people will die.

Here’s a simple calculation that explains this:

In the largest Ebola outbreak in West Africa, there were 28,616 cases of Ebola virus disease and 11,310 deaths, for a death rate of 39.5% (low compared to historic death rates for Ebola Zaire).

If we only had 28,616 cases of COVID-19, at the current death rate of 4.1%, that would translate to 1,173 deaths. But, when you have nearly 600 times as many cases across the world (more than 17.1 million at the time of this writing), because SARS-CoV-2 virus spreads efficiently and we have failed to contain it, even though the death rate is “only” around 4%, that translates to the current number of 669,000 deaths worldwide. As I have said before, infectious disease epidemiology is not rocket science. A ninth grader doing basic algebra could perform that same calculation. Other countries have figured this out. Why hasn’t the United States?

Author Affiliations

From the Institut National de Recherche Biomédicale (P.M.-K., A.N.-N., E.K.-L., A.A., D.M., N.B., D.K., B.N., M.A., O.T., S.M, S.A.-M., J.-J.M.T.), the University of Kinshasa (P.M.-K., A.N.-N., F.M., F.E., M.M., J.B.B., S.A.-M., J.-J.M.T.), and Ministère de la Santé (F.B., V.E., E.S.-P., Y.T.T.N.) — all in Kinshasa, Democratic Republic of Congo the University of Nebraska Medical Center, Omaha (C.P., B.W., M.R.W.) International Medical Corps (M.M.-R.) and the University of California, Los Angeles (A.W.R., M.A.S.), Los Angeles, and the Scripps Research Institute, La Jolla (M.G.P., K.G., E.S., A.T., K.G.A.) — all in California the Fred Hutchinson Cancer Research Center, Seattle (A.B., J.H., T.B.) the Institut Pasteur de Dakar, Dakar, Senegal (M.F., M.M.D., O.F., A.S.) the Vaccine Research Center, National Institutes of Health, Bethesda (J.M., A.P., N.J.S.), and the Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research (I.C.), and the Integrated Research Facility at Fort Detrick, National Institutes of Health (L.H.), Frederick — all in Maryland the World Health Organization, Geneva (B.D., M.K., M.R.D.B., I.S.F., A.Y.) and the University of Edinburgh, Edinburgh, United Kingdom (A.R.).

Address reprint requests to Dr. Mbala-Kingebeni at Institut National de Recherche Biomédicale, 5345, Ave. de la Democratie, B.P. 1187 Gombe, Kinshasa, Democratic Republic of Congo, or at [email protected] or to Dr. Wiley at 984388 Nebraska Medical Center, Omaha, NE 68198-4388, or at [email protected] .

First look at hospitalized Ebola survivors' immune cells could guide vaccine design

In the ongoing Ebola outbreak in West Africa, whose death toll is approaching 10,000, little information has been available about how the human immune response unfolds after infection.

Researchers from Emory and the Centers for Disease Control and Prevention have now obtained a first look at the immune responses in four Ebola virus disease survivors who received care at Emory University Hospital in 2014, by closely examining their T cells and B cells during the acute phase of the disease. The findings reveal surprisingly high levels of immune activation, and have implications for the current effort to develop vaccines against Ebola.

All four patients' immune systems showed strong signs of T and B cell activation, according to a paper published Monday in Proceedings of the National Academy of Sciences. Some previous research on Ebola virus disease had suggested that immune responses could be impaired.

"Our findings counter the idea that Ebola virus infection is immunosuppressive, at least in the patients that we were able to study," says lead author Anita McElroy, MD, assistant professor of pediatrics (infectious disease) at Emory University School of Medicine and a guest researcher at CDC's Viral Special Pathogens Branch. "They also demonstrate the value that supportive care may have in enabling the immune system to fight back against Ebola virus infection."

The paper emerged from a collaboration between immunologists at Emory Vaccine Center led by Rafi Ahmed, PhD, Aneesh Mehta, MD and Emory's Serious Communicable Diseases Unit team, and investigators from CDC's Viral Special Pathogens Branch, led by Christina Spiropoulou, PhD. Researchers from La Jolla Institute for Allergy and Immunology contributed to the paper.

"Until now, detailed studies like this in acute Ebola virus disease were logistically challenging," Ahmed says. "Our work only became possible through a close collaboration with the CDC and use of its biosafety level 4 facilities."

Each patient's level of immune activation reflected the relative intensity of their illnesses. "All four patients have been enthusiastic about participating in research to further knowledge about Ebola," Mehta says. "They have voluntarily donated blood on multiple occasions as part of this research study."

Out of the four patients, the first two became very sick, the third was even sicker and required renal replacement therapy and respiratory support, and the fourth had a milder illness in comparison. While hospitalized, the first three of the patients displayed lymphopenia, or low levels of immune cells in their blood. However, an extraordinarily high proportion of their B and T cells were activated, researchers found. The immune activation continued even after the virus became undetectable in the blood and patients had left the hospital, suggesting that Ebola antigens persist in the body for several weeks.

Scientists tracked patients' B cells, important for generating antibodies against the Ebola virus, and cytotoxic CD8+ T cells, which directly kill infected cells. The patients' CD8+ T cells targeted several proteins, and a major target was an internal Ebola virus protein called NP. However, vaccines now entering clinical trials in Africa contain only the external glycoprotein called GP. This suggests that NP could be added to existing vaccines to generate stronger T cell responses.

"CD8+ T cell responses have been associated with vaccine protection against Ebola infection in some animal models," McElroy says. "But the relative importance of T cell responses, compared to antibody responses, in driving survival and vaccine efficacy in humans is not known. We anticipate it will be an active area of research in the future."

Ahmed is a Georgia Research Alliance Eminent Scholar. The research was supported by the Defense Advanced Research Projects Agency (W31P4Q-14-1-0010) and the National Center for Advancing Translational Sciences (UL1TR000454).


  1. Mazugor

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