Chapter 114. Molecular Mechanisms of Microbial Pathogenesis (Part 10)

InvasionMany diseases are caused primarily by pathogens growing in tissue sites that are normally sterile. Pneumococcal pneumonia is mostly attributable to the growth of S. pneumoniae in the lung and the attendant host inflammatory response, although specific factors that enhance this process (e.g., pneumolysin) may be responsible for some of the pathogenic potential of the pneumococcus. Disease that follows bacteremia and invasion of the meninges by meningitisproducing bacteria such as N. meningitidis, H. influenzae, E. coli K1, and group B streptococci appears to be due solely to the ability of these organisms to gain access to these tissues, multiply...
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Chapter 114. Molecular Mechanisms of Microbial Pathogenesis (Part 10) Chapter 114. Molecular Mechanisms of Microbial Pathogenesis (Part 10) Invasion Many diseases are caused primarily by pathogens growing in tissue sitesthat are normally sterile. Pneumococcal pneumonia is mostly attributable to thegrowth of S. pneumoniae in the lung and the attendant host inflammatoryresponse, although specific factors that enhance this process (e.g., pneumolysin)may be responsible for some of the pathogenic potential of the pneumococcus.Disease that follows bacteremia and invasion of the meninges by meningitis-producing bacteria such as N. meningitidis, H. influenzae, E. coli K1, and group Bstreptococci appears to be due solely to the ability of these organisms to gainaccess to these tissues, multiply in them, and provoke cytokine production leadingto tissue-damaging host inflammation. Specific molecular mechanisms accounting for tissue invasion by fungaland protozoal pathogens are less well described. Except for studies pointing tofactors like capsule and melanin production by C. neoformans and (possibly)levels of cell wall glucans in some pathogenic fungi, the molecular basis for fungalinvasiveness is not well defined. Melanism has been shown to protect the fungalcell against death caused by phagocyte factors such as nitric oxide, superoxide,and hypochlorite. Morphogenic variation and production of proteases (e.g., theCandida aspartyl proteinase) have been implicated in fungal invasion of hosttissues. If pathogens are effectively to invade host tissues (particularly the blood),they must avoid the major host defenses represented by complement andphagocytic cells. Bacteria most often avoid these defenses through their cellsurface polysaccharides—either capsular polysaccharides or long O-side-chainantigens characteristic of the smooth LPS of gram-negative bacteria. Thesemolecules can prevent the activation and/or deposition of complement opsonins orlimit the access of phagocytic cells with receptors for complement opsonins tothese molecules when they are deposited on the bacterial surface below thecapsular layer. Another potential mechanism of microbial virulence is the abilityof some organisms to present the capsule as an apparent self antigen throughmolecular mimicry. For example, the polysialic acid capsule of group B N.meningitidis is chemically identical to an oligosaccharide found on human braincells. Immunochemical studies of capsular polysaccharides have led to anappreciation of the tremendous chemical diversity that can result from the linkingof a few monosaccharides. For example, three hexoses can link up in more than300 different and potentially serologically distinct ways, while three amino acidshave only six possible peptide combinations. Capsular polysaccharides, whichhave been used as effective vaccines against meningococcal meningitis as well asagainst pneumococcal and H. influenzae infections, may prove to be of value asvaccines against any organisms that express a nontoxic, immunogenic capsularpolysaccharide. In addition, most encapsulated pathogens become virtuallyavirulent when capsule production is interrupted by genetic manipulation; thisobservation emphasizes the importance of this structure in pathogenesis. Host Response The inflammatory response of the host is critical for interruption andresolution of the infectious process but also is often responsible for the signs andsymptoms of disease. Infection promotes a complex series of host responsesinvolving the complement, kinin, and coagulation pathways. The production ofcytokines such as IL-1, TNF-α, and other factors regulated in part by the NF-κBtranscription factor leads to fever, muscle proteolysis, and other effects, as notedabove. An inability to kill or contain the microbe usually results in further damagedue to the progression of inflammation and infection. In many chronic infections,degranulation of host inflammatory cells can lead to release of host proteases,elastases, histamines, and other toxic substances that can degrade host tissues.Chronic inflammation in any tissue can lead to the destruction of that tissue and toclinical disease associated with loss of organ function; an example is sterility frompelvic inflammatory disease caused by chronic infection with N. gonorrhoeae. The nature of the host response elicited by the pathogen often determinesthe pathology of a particular infection. Local inflammation produces local tissuedamage, while systemic inflammation, such as that seen during sepsis, can resultin the signs and symptoms of septic shock. The severity of septic shock isassociated with the degree of production of host effectors. Disease due tointracel ...