The pneumococcus is the classic Gram-positive extracellular pathogen. The medical burden of diseases it causes is amongst the greatest in the world. Intense study for more than 100 years has yielded ...an understanding of fundamental aspects of its physiology, pathogenesis, and immunity. Efforts to control infection have led to the deployment of polysaccharide vaccines and an understanding of antibiotic resistance. The inflammatory response to pneumococci, one of the most potent in medicine, has revealed the double-edged sword of clearance of infection but at a cost of damage to host cells. In virtually every aspect of the infectious process, the pneumococcus has set the rules of the Gram-positive pathogenesis game.
Streptococcus pneumoniae
is an opportunistic pathogen responsible for widespread illness and is a major global health issue for children, the elderly, and the immunocompromised population. ...Pneumolysin (PLY) is a cholesterol-dependent cytolysin (CDC) and key pneumococcal virulence factor involved in all phases of pneumococcal disease, including transmission, colonization, and infection. In this review we cover the biology and cytolytic function of PLY, its contribution to
S. pneumoniae
pathogenesis, and its known interactions and effects on the host with regard to tissue damage and immune response. Additionally, we review statins as a therapeutic option for CDC toxicity and PLY toxoid as a vaccine candidate in protein-based vaccines.
Streptococcus pneumoniae (the pneumoccus) is the leading cause of otitis media, community-acquired pneumonia, and bacterial meningitis. The success of the pneumococcus stems from its ability to ...persist in the population as a commensal and avoid killing by immune system. This chapter first reviews the molecular mechanisms that allow the pneumococcus to colonize and spread from one anatomical site to the next. Then, it discusses the mechanisms of inflammation and cytotoxicity during emerging and classical pneumococcal infections.
Bacterial pathogens produce complex carbohydrate capsules to protect against bactericidal immune molecules. Paradoxically, the pneumococcal capsule sensitizes the bacterium to antimicrobial peptides ...found on epithelial surfaces. Here we show that upon interaction with antimicrobial peptides, encapsulated pneumococci survive by removing capsule from the cell surface within minutes in a process dependent on the suicidal amidase autolysin LytA. In contrast to classical bacterial autolysis, during capsule shedding, LytA promotes bacterial survival and is dispersed circumferentially around the cell. However, both autolysis and capsule shedding depend on the cell wall hydrolytic activity of LytA. Capsule shedding drastically increases invasion of epithelial cells and is the main pathway by which pneumococci reduce surface bound capsule during early acute lung infection of mice. The previously unrecognized role of LytA in removing capsule to combat antimicrobial peptides may explain why nearly all clinical isolates of pneumococci conserve this enzyme despite the lethal selective pressure of antibiotics.
Hospitalization of the elderly for invasive pneumococcal disease is frequently accompanied by the occurrence of an adverse cardiac event; these are primarily new or worsened heart failure and cardiac ...arrhythmia. Herein, we describe previously unrecognized microscopic lesions (microlesions) formed within the myocardium of mice, rhesus macaques, and humans during bacteremic Streptococcus pneumoniae infection. In mice, invasive pneumococcal disease (IPD) severity correlated with levels of serum troponin, a marker for cardiac damage, the development of aberrant cardiac electrophysiology, and the number and size of cardiac microlesions. Microlesions were prominent in the ventricles, vacuolar in appearance with extracellular pneumococci, and remarkable due to the absence of infiltrating immune cells. The pore-forming toxin pneumolysin was required for microlesion formation but Interleukin-1β was not detected at the microlesion site ruling out pneumolysin-mediated pyroptosis as a cause of cell death. Antibiotic treatment resulted in maturing of the lesions over one week with robust immune cell infiltration and collagen deposition suggestive of long-term cardiac scarring. Bacterial translocation into the heart tissue required the pneumococcal adhesin CbpA and the host ligands Laminin receptor (LR) and Platelet-activating factor receptor. Immunization of mice with a fusion construct of CbpA or the LR binding domain of CbpA with the pneumolysin toxoid L460D protected against microlesion formation. We conclude that microlesion formation may contribute to the acute and long-term adverse cardiac events seen in humans with IPD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We assessed the ability of Streptococcus pneumoniae mutants deficient in either choline binding protein A (CbpA), pneumolysin (Pln), pyruvate oxidase (SpxB), autolysin (LytA), pneumococcal surface ...protein A, or neuraminidase A (NanA) to replicate in distinct anatomical sites and translocate from one site to the next. Intranasal, intratracheal, and intravenous models of disease were assessed in 4-week-old BALB/cJ mice by quantitation of bacterial titers in the relevant organs. Mice were also observed by use of real-time bioluminescent imaging (BLI). BLI allowed visualization of the bacteria in sites not tested by sampling. All mutants were created in D39 Xen7, a fully virulent derivative of capsular type 2 strain D39 that contains an optimized luxABCDE cassette. NanA, SpxB, and, to a lesser extent, CbpA contributed to prolonged nasopharyngeal colonization, whereas CbpA and NanA contributed to the transition to the lower respiratory tract. Once lung infection was established, Pln, SpxB, and LytA contributed to bacterial replication in the lungs and translocation to the bloodstream. In the bloodstream, only Pln and LytA were required for high-titer replication, whereas CbpA was required for invasion of the cerebrospinal fluid. We conclude that transitions between body sites require virulence determinants distinct from those involved in organ-specific replication.
Highly successful invasive pathogens exploit host vulnerabilities by adapting tools to co-opt highly conserved host features. This is especially true when pathogens develop ligands to hijack ...trafficking routes or signaling patterns of host receptors. In this context, highly successful pathogens can be grouped together by the patterns of organs infected and diseases they cause. In the case of this perspective, the focus is on the historically most successful invasive bacterial pathogens of children that cause pneumonia, sepsis and meningitis:
, and
. This triad shares a ligand to bind to PAF receptor to enter host cells despite early defenses by innate immunity. All three also target laminin receptor to cross endothelial barriers using a common set of molecular tools that may prove to be a design for a cross-protective vaccine.
Small noncoding RNAs (sRNAs) play important roles in gene regulation in both prokaryotes and eukaryotes. Thus far, no sRNA has been assigned a definitive role in virulence in the major human pathogen ...Streptococcus pneumoniae. Based on the potential coding capacity of intergenic regions, we hypothesized that the pneumococcus produces many sRNAs and that they would play an important role in pathogenesis. We describe the application of whole-genome transcriptional sequencing to systematically identify the sRNAs of Streptococcus pneumoniae. Using this approach, we have identified 89 putative sRNAs, 56 of which are newly identified. Furthermore, using targeted genetic approaches and Tn-seq transposon screening, we demonstrate that many of the identified sRNAs have important global and niche-specific roles in virulence. These data constitute the most comprehensive analysis of pneumococcal sRNAs and provide the first evidence of the extensive roles of sRNAs in pneumococcal pathogenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Bacterial meningitis is a devastating disease occurring worldwide with up to half of the survivors left with permanent neurological sequelae. Due to intrinsic properties of the meningeal pathogens ...and the host responses they induce, infection can cause relatively specific lesions and clinical syndromes that result from interference with the function of the affected nervous system tissue. Pathogenesis is based on complex host–pathogen interactions, some of which are specific for certain bacteria, whereas others are shared among different pathogens. In this review, we summarize the recent progress made in understanding the molecular and cellular events involved in these interactions. We focus on selected major pathogens,
Streptococcus pneumonia
,
S. agalactiae
(Group B Streptococcus),
Neisseria meningitidis
, and
Escherichia coli
K1, and also include a neglected zoonotic pathogen,
Streptococcus suis
. These neuroinvasive pathogens represent common themes of host–pathogen interactions, such as colonization and invasion of mucosal barriers, survival in the blood stream, entry into the central nervous system by translocation of the blood–brain and blood–cerebrospinal fluid barrier, and induction of meningeal inflammation, affecting pia mater, the arachnoid and subarachnoid spaces.
Toll-like receptor (TLR) signaling in macrophages is required for antipathogen responses, including the biosynthesis of nitric oxide from arginine, and is essential for immunity to Mycobacterium ...tuberculosis, Toxoplasma gondii and other intracellular pathogens. Here we report a 'loophole' in the TLR pathway that is advantageous to these pathogens. Intracellular pathogens induced expression of the arginine hydrolytic enzyme arginase 1 (Arg1) in mouse macrophages through the TLR pathway. In contrast to diseases dominated by T helper type 2 responses in which Arg1 expression is greatly increased by interleukin 4 and 13 signaling through the transcription factor STAT6, TLR-mediated Arg1 induction was independent of the STAT6 pathway. Specific elimination of Arg1 in macrophages favored host survival during T. gondii infection and decreased lung bacterial load during tuberculosis infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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