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How host defends against S. pneumoniae capsule?

How host defends against S. pneumoniae capsule?


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The host response involves at least phagocytosis and probably localised acute inflammatory response at least after the colonisation.

I am thinking how the host can defend against pneumolysin which helps the streptococcus pneumoniae invasion.

How can the host defend against Streptococcus pneumoniae capsule?


According to the two papers listed below, this is mostly done by a neutrophilic inflammatory response. The response is regulated by mechanisms of the innate immune system and is mediated by receptor like TLR2, TLR4 and SIGN-R1.

There are a few papers which go deeper (reviews, so you will probably have to go through the reference lists):

This paper mentions specific antibodies later on in the reaction and finally the opsonization by immune cells.

These two papers tal specifically about pneumolysin:


Bacterial Capsules

Regulation of Capsular Synthesis

It is well documented that the levels of bacterial capsules vary under various environmental conditions, such as temperature as in the group 2 and 3 CPSs, and colanic acid of E. coli [142] , oxygen tension as in the alginate capsule of P. aeruginosa [143] , or concentration of certain ions as in the hyaluronic acid capsule of S. pyogenes [30] . A number of regulatory systems for capsule production have been identified and characterized to various extents in many pathogens. These and other lines of information have revealed several common strategies that different pathogens use to control the capsule level.


STREPTOCOCCUS PNEUMONIAE: pathogenesis, Lab diagnosis, treatment

Streptococcus pneumoniaeis a Gram-positive, capsular, non-motile and catalase-negative cocci that are usually lancet (bullet) shaped. S. pneumoniae also occurs in pairs (as diplococci) or in chains (as streptococci) and they are haemolytic in nature and inhibited by optochin. A member of the normal flora of the human upper respiratory tract system, S. pneumoniae (commonly referred to as pneumococcus), is notorious in causing a range of infections in human population. It is the most common cause of community acquired pneumonia in humans. Other infections in which S. pneumoniae is implicated are osteomyelitis, abscesses, otitis media, meningitis, bacteraemia, peritonitis, endocarditis and cellulitis.

Virulent strains of S. pneumoniae have surface capsules composed mainly of high-molecular monosaccharides and oligosaccharides that interfere with phagocytosis. The upper respiratory tract of humans is the main reservoir of pneumococci, and they can be spread to susceptible hosts via respiratory droplets or aerosols emanating from the respiratory secretions of infected individuals. Pneumococci colonize the upper respiratory tract without causing any disease, but infection ensues following weakened immune system and poor state of health. Pneumonia caused by S. pneumoniae is most prevalent amongst certain individuals with some predisposing factors such as prior viral infection of the respiratory tract, history of alcoholism, drug intoxication, and injury to the respiratory tract, as well as heart failure, diabetes and old age. People with these underlying health conditions are more prone to infection with pneumococcus than those whose health status are still intact and have strong immune system.

PATHOGENESIS OF STREPTOCOCCUS PNEUMONIAE INFECTION

Pneumonia (a reduced function of the lungs) is a lung disease that is caused by certain pathogenic bacteria species including S. pneumoniae (pneumococcus). Other bacteria species that cause human pneumonia are Staphylococci, Haemophilus, Pseudomonas, Mycoplasma and Chlamydia. Non-bacterial causes of pneumonia are some species of viruses, fungi and protozoa. The virulence of infection caused by S. pneumoniae is usually determined by some virulent factors such as pili, capsules, cell wall surface proteins (teichoic acid and peptidoglycan), haemolysins, hydrogen peroxides and autolysins released by the pathogen during an infection. The onset of pneumonia in humans starts following the aspiration of respiratory secretions or droplets that contains virulent strains of S. pneumoniae.Upon invasion and possible colonization of the upper respiratory tract where they normally inhabit, S. pneumoniae reaches the lower respiratory tract where they attack the alveolar cells of the lungs and produce a variety of lung diseases. S. pneumoniae multiplies rapidly in the alveolar spaces, and produce inflammatory cells which fills the alveoli spaces and/or lungs.

Systemic infections due to pneumococcus occur when S. pneumoniae reaches the body’s blood circulation via the lymphatic vessels of the lungs. S. pneumoniae can reach other sites of the body such as the middle ear, heart and meninges via the respiratory tract and produce further clinical complications. Fever, chills, chest pain, difficulty in breathing and expectoration of sputum usually accompanied with blood (i.e., rusty coloured blood) are some of the clinical signs and symptoms associated with pneumonia caused by S. pneumoniae. Bronchial pneumonia and lobar pneumonia are the two types of pneumonia caused by pneumococcus in humans. Bronchial pneumonia is common in old people, young children and infants while lobar pneumonia is commonly experienced by young adults. Uncapsulated strains of pneumococcus are generally avirulent, and are not capable of producing pneumonia in humans. Only the capsulated S. pneumoniae strains actually produce the clinical episodes of the disease, and this is because capsulated pneumococci have polysaccharide capsules that protect them from phagocytosis.

LABORATORY DIAGNOSIS OF STREPTOCOCCUS PNEUMONIAE INFECTION

The laboratory diagnosis of pneumonia caused by S. pneumoniae is mainly based on the identification and isolation of the pathogen from patient’s specimens via microscopy and culture techniques. Sputum, CSF, exudates and blood specimens are usually the main samples collected when pneumococcal pneumonia is suspected. Gram stained smear of sputum samples reveals Gram-positive lancet (bullet) shaped diplococci. S. pneumoniae is a fastidious bacterium, and they grow best in culture media supplemented with horse, rabbit or human blood and incubated in 5% carbon dioxide. On blood agar, S. pneumoniae produce mucoid or translucent colonies that are alpha haemolytic and pneumococcus is optochin sensitive and soluble to bile salts. Pneumococcus ferment glucose to produce lactic acid. Serologically, S. pneumoniae is positive to the quellung reaction test also known as the swelling reaction. In quellung reaction test which is used to determine the polysaccharide capsule of S. pneumoniae, the capsules of pneumococcus swells markedly when the pathogen is mixed with certain specific antiserum and then examined microscopically at a magnification of 1000X for capsular swelling. Quellung reaction test is usually used for the rapid detection of pneumococcus from cultures and sputum samples in the microbiology laboratory.

IMMUNITY TO STREPTOCOCCUS PNEUMONIAE INFECTION

Immunity against pneumococcus is strain-type specific. There are about 90 different serotypes or antigenic variants of pneumococcus. Protection against pneumococcal pneumonia or any of the pathogenic strains of the pathogen is usually based on intact phagocytic function of the host’s immune system, and on antibody production against the capsular polysaccharide of S. pneumoniae. Antibody production by the host enhances phagocytosis or opsonization of the invading bacteria or pneumococcus. However, a lasting natural form of immunity after prior infection cannot be established, which is why pneumococcal pneumonia can occur throughout a person’s lifetime especially in young adults, the elderly and people with a debilitated immunity or other forms of underlying disease conditions.

TREATMENT OF STREPTOCOCCUS PNEUMONIAE INFECTION

Pneumonia caused by pneumococcus is stopped abruptly when the right antimicrobial agents are administered early. Penicillins V and G, vancomycin, cephalosporins, macrolides and quinolones are some of the antibiotics classes used to treat and manage pneumococcal pneumonia. Some strains of pneumococcus may be resistant to some first-line antibiotics such as penicillins, thus antibiotic therapy should be guided by the results of susceptibility studies.

PREVENTION AND CONTROL OF STREPTOCOCCUS PNEUMONIAE

Pneumococcal pneumonia is typically an endemic respiratory infection that occurs occasionally in human populations (who are the main reservoirs of the causative agent). S. pneumoniae is a transient member of the human normal flora and the organism colonizes the upper respiratory tract (nasopharynx) of both children and healthy adults who harbour pneumococcus asymptomatically. Mortality due to pneumococcal pneumonia is usually high in the elderly, people with impaired natural resistance against the pathogen (e.g., sickle cell patients), and in the debilitated or immunocompromised individuals. Such individuals should be properly vaccinated against the disease and its causative agent since immunization confers a lasting form of protection. The prevention of pneumococcal pneumonia is largely based on immunization using pneumococcal vaccine and the effective treatment of affected individuals. About 90 virulent strains of S. pneumoniae are known, and there exist effective vaccines (Pneumovax 23) for the prevention of a handful of the pneumococcal strains that cause pneumonia in humans (especially the elderly and debilitated people). A seven-valent conjugate vaccine for immunization in children under the age of two years is also available and effective. People at high risk of having respiratory tract infections, those with weakened immunity, the elderly and healthcare personnel’s should be vaccinated against pneumococcus. Pneumovax 23 is believed to help increase host phagocytic action against the capsulated pneumococcus.People should avoid factors that can predispose them to the disease, and treatment should be started early once pneumococcal pneumonia is suspected.

Further reading

Brooks G.F., Butel J.S and Morse S.A (2004). Medical Microbiology, 23 rd edition. McGraw Hill Publishers. USA.

Gilligan P.H, Shapiro D.S and Miller M.B (2014). Cases in Medical Microbiology and Infectious Diseases. Third edition. American Society of Microbiology Press, USA.

Madigan M.T., Martinko J.M., Dunlap P.V and Clark D.P (2009). Brock Biology of Microorganisms, 12 th edition. Pearson Benjamin Cummings Inc, USA.

Mahon C. R, Lehman D.C and Manuselis G (2011). Textbook of Diagnostic Microbiology. Fourth edition. Saunders Publishers, USA.

Patrick R. Murray, Ellen Jo Baron, James H. Jorgensen, Marie Louise Landry, Michael A. Pfaller (2007). Manual of Clinical Microbiology, 9th ed.: American Society for Microbiology.

Wilson B. A, Salyers A.A, Whitt D.D and Winkler M.E (2011). Bacterial Pathogenesis: A molecular Approach. Third edition. American Society of Microbiology Press, USA.

Woods GL and Washington JA (1995). The Clinician and the Microbiology Laboratory. Mandell GL, Bennett JE, Dolin R (eds): Principles and Practice of Infectious Diseases. 4th ed. Churchill Livingstone, New York.


Capsule and d -alanylated lipoteichoic acids protect Streptococcus pneumoniae against neutrophil extracellular traps

Department of Bacteriology, Swedish Institute for Infectious Disease Control, Solna, Sweden.

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.

These authors contributed equally to this work.

Department of Bacteriology, Swedish Institute for Infectious Disease Control, Solna, Sweden.

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.

These authors contributed equally to this work.

Department of Bacteriology, Swedish Institute for Infectious Disease Control, Solna, Sweden.

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.

Department of Bacteriology, Swedish Institute for Infectious Disease Control, Solna, Sweden.

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.

Department of Cellular Microbiology, Max-Planck Institute for Infection Biology, Berlin, Germany.

Department of Bacteriology, Swedish Institute for Infectious Disease Control, Solna, Sweden.

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.

Department of Bacteriology, Swedish Institute for Infectious Disease Control, Solna, Sweden.

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.

Department of Bacteriology, Swedish Institute for Infectious Disease Control, Solna, Sweden.

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.

These authors contributed equally to this work.

Department of Bacteriology, Swedish Institute for Infectious Disease Control, Solna, Sweden.

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.

These authors contributed equally to this work.

Department of Bacteriology, Swedish Institute for Infectious Disease Control, Solna, Sweden.

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.

Department of Bacteriology, Swedish Institute for Infectious Disease Control, Solna, Sweden.

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.

Department of Cellular Microbiology, Max-Planck Institute for Infection Biology, Berlin, Germany.

Department of Bacteriology, Swedish Institute for Infectious Disease Control, Solna, Sweden.

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.

Department of Bacteriology, Swedish Institute for Infectious Disease Control, Solna, Sweden.

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.

Summary

Streptococcus pneumoniae is a major cause of morbidity and mortality worldwide. Pneumococci can counteract the action of neutrophils with an antiphagocytic capsule and through electrochemical repulsion of antimicrobial peptides via addition of positive charge to the surface. Pneumococci are captured, but not killed in neutrophil extracellular traps (NETs). Here, we study the role of the polysaccharide capsule and lipoteichoic acid (LTA) modification on pneumococcal interaction with NETs. Expression of capsule (serotypes 1, 2, 4 and 9V) significantly reduced trapping by NETs, but was not required for resistance to NET-mediated killing. Pneumococci contain a dlt operon that mediates the incorporation of d -alanine residues into LTAs, thereby introducing positive charge. Genetic inactivation of dltA in non-encapsulated pneumococci rendered the organism sensitive to killing by antimicrobial components present in NETs. However, the encapsulated dltA mutant remained resistant to NET-mediated killing in vitro. Nevertheless, in a murine model of pneumococcal pneumonia, the encapsulated dltA-mutant strain was outcompeted by the wild-type upon invasion into the lungs and bloodstream. This suggests a non-redundant role for LTA alanylation in pneumococcal virulence at the early stage of invasive disease when capsule expression has been shown to be low.

Figure S1. Only non-encapsulated pneumococci are phagocytosed by polymorphonuclear leukocytes (PMNs), a process that can be efficiently blocked by Cytochalasin D. A. Neutrophils were stimulated for NET formation and infected with encapsulated and non-encapsulated TIGR4 pneumococci at a MOI of 10. Half of the samples were treated with 10 μg ml -1 Cytochalasin D to block phagocytosis. Thirty minutes post-infection, the samples were fixed and stained for DNA (blue) and neutrophil elastase (red). S. pneumoniae were labeled with FITC before addition (green). Scale bars represent 20 μm. Phagocytosis of non-encapsulated bacteria (shown in inset) was observed in the absence of Cytochalasin D. Addition of Cytochalasin D inhibited this process efficiently. The mean numbers of bacteria (plus standard deviations) per cell were quantified for each strain in the absence (B) or presence (C) of Cytochalasin D. The non-parametric Mann-Whitney test was used for statistical comparison between encapsulated and non-encapsulated strains. Figure S2. Phagocytosis inhibition by Cytochalasin D does not influence bacteria-NET-interaction. The number of bacteria per μm of NET filament five min p.i. was determined in the presence (white) or absence (black) of 10 μg ml -1 Cytochalasin D. Mean values and standard deviations (SD) are shown. Trapped bacteria in pictures with filamentous NET structures were counted manually and the NET filament length was determined with the Zeiss LSM Image Browser software. The paired t-test was used for statistical comparison between with and without Cytochalasin D treatment for each strain. Cytochalasin D treatment did not affect the interaction of pneumococci with NETs in terms of trapping.

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Defects in Host Defense Mechanisms

Two types of immune deficiency states affect the host’s ability to fight infection:

Primary immune deficiencies are genetic in origin > 100 primary immune deficiency states have been described. Most primary immune deficiencies are recognized during infancy however, up to 40% are first recognized during adolescence or adulthood.

Acquired immune deficiencies are caused by another disease (eg, cancer, HIV infection, chronic disease) or by exposure to a chemical or drug that is toxic to the immune system.

Mechanisms

Defects in immune responses may involve

Cellular deficiencies are typically T-cell or combined immune defects. T cells contribute to the killing of intracellular organisms thus, patients with T-cell defects can present with opportunistic infections such as Pneumocystis jirovecii or cryptococcal infections. Chronicity of these infections can lead to failure to thrive, chronic diarrhea, and persistent oral candidiasis.

Humoral deficiencies are typically caused by the failure of B cells to make functioning immunoglobulins. Patients with this type of defect usually have infections involving encapsulated organisms (eg, H. influenzae, S. pneumoniae). Patients can present with poor growth, diarrhea, and recurrent sinopulmonary infections.

A defect in the phagocytic system affects the immediate immune response to bacterial infection and can result in development of recurrent abscesses or severe pneumonias.

Primary complement system defects are particularly rare. Patients with this type of defect may present with recurrent infections with pyogenic bacteria (eg, encapsulated bacteria, Neisseria species) and have an increased risk of autoimmune disorders (eg, systemic lupus erythematosus).


Polysaccharide capsule

  • all clinical isolates of S. pneumoniae causing invasive disease are encapsulated
  • loss of the capsule by either genetic mutation or enzymatic degradation dramatically reduces S. pneumoniae virulence in animal models of infection
  • different capsular serotypes vary in the ability to cause invasive disease

The capsule may inhibit complement activity (capsule impaired bacterial opsonization with C3b/iC3b by both the alternative and classical complement pathways and also inhibited conversion of C3b bound to the bacterial surface to iC3b) and phagocytosis. Capsule also prevents mechanical removal by mucus and reduce exposure to antibiotics

For S. pneumoniae strains, there are >93 antigenically distinct capsular serotypes and antibody to the polysaccharide capsule provides type-specific immunity.


Structure and Composition

Capsule is a gelatinous layer covering the entire bacterium. In light microscopy, capsules appear to be amorphous gelatinous areas surrounding the cell. Capsule is located immediately exterior to the murein (peptidoglycan) layer of gram-positive bacteria and the outer membrane (Lipopolysaccharide layer) of gram-negative bacteria. In electron microscopy, capsule appears like a mesh or network of fine strands.

Most bacterial capsules are composed of polysaccharides (i.e. poly: many, saccharide: sugar). These polymers are composed of repeating oligosaccharide units of two to four monosaccharides. Capsules composed of single kinds of sugars are termed homopolysaccharides. For example, the capsule of Streptococcus mutans is made up of glucose polymers. If several kinds of sugars are present in a capsule, then it is called heteropolysaccharides, eg., the capsule of Klebsiella pneumoniae. The capsule of Bacillus anthracis is an exception. This polypeptide capsule is composed of polymerized D-glutamic acid.

The sugar components of polysaccharides vary within the species of bacteria, which determines their serologic types. Example: Streptococcus pneumoniae has 84 different serotypes discovered so far.


Pathology

Streptococcus pneumoniae is known to cause bacteremia, otitis media, and meningitis in humans, though it is best known for causing pneumonia, a disease of the upper respiratory tract that causes illness and death all over the world. (5) Symptoms of pneumonia include a cough accompanied by greenish or yellow mucous, fever, chills, shortness of breath, and chest pain. The bacteria enter the body most commonly via inhalation of small water droplets. Very young children and the elderly are the most prone to catching pneumonia.

The virulence factors of S. pneumoniae include a plysaccharide capsule that prevents phagocytosis by the host's immune cells (5), surface proteins that prevent the activation of complement (part of the immune system that helps clear pathogens from the body), and pili that enable S. pneumoniae to attach to epithelial cells in the upper respiratory tract. (4)

The polysaccharide capsule interferes with phagocytosis through its chemical composition, resisting by interfering with binding of complement C3b to the cell's surface. Encapsulated strains of S. pneumoniae are found to be 100,000 times more virulent than unencapsulated strains during invasion of mucosal surfaces. (5) Virulence is a harmful quality possessed by microorganisms that can cause disease, and the characteristics of encapsulated strains are essentially the key to virulence. Being encapsulated is advantageous for bacteria, since the capsule is in most cases antiphagocytic, meaning it prevents phagocytosis. It is also antigenic as it stimulates the production of an antibody when introduced into the body. Encapsualted S.pneumoniae strains have caused large conjunctivitis outbreaks in schools, military training facilities, and at other locations worldwide (Valentino et al., 2014). However, recent studies of epidemiologically unrelated conjunctivitis cases found that most cases were caused by encapsulated strains.

Pili are long, thin extracellular organelles that are able to extend outside of the polysaccharide capsule. They are encoded by the rlrA islet (an area of a genome in which rapid mutation takes place) which is present in only some isolated strains of S. pneumoniae. These pili contribute to adherence and virulence, as well as increase the inflammatory response of the host. (4)


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Research output : Contribution to journal › Article › peer-review

T1 - Macrophage LC3-associated phagocytosis is an immune defense against Streptococcus pneumoniae that diminishes with host aging

N1 - Funding Information: ACKNOWLEDGMENTS. We thank Elsa Bou Ghanem, Sara Roggensack, Marcia Osburne, Nalat Siwapornchai, and Dawn Bowdish for helpful experimental advice and/or invaluable discussion in the preparation of the paper H. W. Virgin (WUSM), M. Dinauer (WUSM), and D. Young (St. Jude Children’s Research Hospital, Memphis, TN) for their generosity in providing mice Hitoshi Iwahashi (Gifu University) for mouse experiment cooperation and Greg Hendricks and Lara Strittmatter at the UMass Medical School Electron Microscopy Core for technical advice. This work was supported by a Grant-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science to M.I. (18K09544), the Pott’s Memorial Foundation to P.C., and NIH/National Institute of Allergy and Infectious Diseases R01s (Grant AI087682, Grant AI130454) to J.A.P. Publisher Copyright: © 2020 National Academy of Sciences. All rights reserved.

N2 - Streptococcus pneumoniae is a leading cause of pneumonia and invasive disease, particularly, in the elderly. S. pneumoniae lung infection of aged mice is associated with high bacterial burdens and detrimental inflammatory responses. Macrophages can clear microorganisms and modulate inflammation through two distinct lysosomal trafficking pathways that involve 1A/1B-light chain 3 (LC3)-marked organelles, canonical autophagy, and LC3-associated phagocytosis (LAP). The S. pneumoniae pore-forming toxin pneumolysin (PLY) triggers an autophagic response in nonphagocytic cells, but the role of LAP in macrophage defense against S. pneumoniae or in age-related susceptibility to infection is unexplored. We found that infection of murine bone-marrow-derived macrophages (BMDMs) by PLY-producing S. pneumoniae triggered Atg5- and Atg7-dependent recruitment of LC3 to S. pneumoniae-containing vesicles. The association of LC3 with S. pneumoniae-containing phagosomes required components specific for LAP, such as Rubicon and the NADPH oxidase, but not factors, such as Ulk1, FIP200, or Atg14, required specifically for canonical autophagy. In addition, S. pneumoniae was sequestered within single-membrane compartments indicative of LAP. Importantly, compared to BMDMs from young (2-mo-old) mice, BMDMs from aged (20- to 22-mo-old) mice infected with S. pneumoniae were not only deficient in LAP and bacterial killing, but also produced higher levels of proinflammatory cytokines. Inhibition of LAP enhanced S. pneumoniae survival and cytokine responses in BMDMs from young but not aged mice. Thus, LAP is an important innate immune defense employed by BMDMs to control S. pneumoniae infection and concomitant inflammation, one that diminishes with age and may contribute to age-related susceptibility to this important pathogen.

AB - Streptococcus pneumoniae is a leading cause of pneumonia and invasive disease, particularly, in the elderly. S. pneumoniae lung infection of aged mice is associated with high bacterial burdens and detrimental inflammatory responses. Macrophages can clear microorganisms and modulate inflammation through two distinct lysosomal trafficking pathways that involve 1A/1B-light chain 3 (LC3)-marked organelles, canonical autophagy, and LC3-associated phagocytosis (LAP). The S. pneumoniae pore-forming toxin pneumolysin (PLY) triggers an autophagic response in nonphagocytic cells, but the role of LAP in macrophage defense against S. pneumoniae or in age-related susceptibility to infection is unexplored. We found that infection of murine bone-marrow-derived macrophages (BMDMs) by PLY-producing S. pneumoniae triggered Atg5- and Atg7-dependent recruitment of LC3 to S. pneumoniae-containing vesicles. The association of LC3 with S. pneumoniae-containing phagosomes required components specific for LAP, such as Rubicon and the NADPH oxidase, but not factors, such as Ulk1, FIP200, or Atg14, required specifically for canonical autophagy. In addition, S. pneumoniae was sequestered within single-membrane compartments indicative of LAP. Importantly, compared to BMDMs from young (2-mo-old) mice, BMDMs from aged (20- to 22-mo-old) mice infected with S. pneumoniae were not only deficient in LAP and bacterial killing, but also produced higher levels of proinflammatory cytokines. Inhibition of LAP enhanced S. pneumoniae survival and cytokine responses in BMDMs from young but not aged mice. Thus, LAP is an important innate immune defense employed by BMDMs to control S. pneumoniae infection and concomitant inflammation, one that diminishes with age and may contribute to age-related susceptibility to this important pathogen.



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