Bordetella pertussis in a complex, multifactoral disease. It seems suiting, then, that it has developed a means of supressing of altering the host immune response to prolong its survival in a complex manner, utilizing many evasive and immunomodulatory mechanisms. The most direct evidence of the evasion or subversion of host immune responses is the delayed T cell and antibody response coupled with suppression of intracellular phagocytic killing (McGuirk et al. 1998, Mills et al. 1993, Saukkonen et al. 1991, Steed et al. 1992). The ability of B. pertussis to perform this immunosuppression finds its source in the many different virulence factors associated with a pertussis infection. While several virulence factors (FHA, PRN, fimbriae) may help the bacteria to attach to respiratory epithelium, they can also help inhibit or induce cytokines or effector cell mechanisms that promote bacteria survival. For a detailed account of the immunomodulatory effects of various virulence factors, see the table below. Moreover, the occupation of an intracellular niche by B. pertussis allows it to avoid many arms of the immune response, including the threat of circulating antibodies (Fedele et al 2005).
Antibodies do seem to play role the immune response to B. pertussis, and they may do so in three ways: neutralization of toxins, the inhibition of binding by extracellular pertussis, and the facilitation of uptake by phagocytes. Antibody coated bacteria can activate the complement system. The bacterial protein BrkA, however, provides resistance to complement-mediated killing (Fernandez and Weiss 1998). Opsonization may also facilitate uptake by macrophages, within which bacteria can survive and evade immune responses (Mills 2001). Within human monocytes, due partly to the virulence factor pertussis toxin, HLA-DR expression is altered (Sumilla et al. 2004).
Cell-mediated immunity controls the most important branch of the immune response to clear B. pertussis infection. Infection selectively activates a dominantly TH1 response (Mills et al. 2001). While this polarization reflects the necessity of extracellular and intracellular clearance mechanisms, it also means that humoral immunity is less extensive than cell-mediated immunity. The polarization of the TH1 response is mediated by cytokines, and B. pertussis, along with its virulence factors, can influence the cytokine environment to promote its survival. While not fully worked out, three different mechanisms for the down-regulation of cell mediated immunity may play a role. (1) Murine models have shown a decrease in the co-stimulatory protein CD28 on T cells in lungs of infected individuals (McGuirk et al. 1998). (2) Suppression of T cell effector mechanisms may occur by bacterial induction of T regulatory (Treg) cells (Mcguirk and Mills 2000). (3) Induction of regulatory cytokine production by virulence factors. The actual mechanism is most likely some combination of these factors. Pertussis LPS has been shown to induce production of IL-10 and Treg cell differentiation. The complexity of this bacterial infection, however, is evidenced by increased bacterial loads in IL-10 knockout mice, despite increased TH1 response (Higgins et al. 2003).
Virulence factors have shown functions, aside from cytokine modulation, that promote survival of B. pertussis. The migration of neutrophils activated by TLR signaling via binding LPS, a virulence factor of B. pertussis, can be blocked by PT (Thomazzi et al. 1995). Apoptosis of lung cells by adenylate cyclase toxin is reflected in a seven-day delay in macrophage influx (Gueirard et al. 1998).
The many pertussis antigens interact with the host immune response in a complex, and not fully described manner. Mutations in antigenic epitopes, however, may indicate antigenic variation as a means of evading host protection (Mills 2001). Moreover, there is some evidence that supports the presence of escape variants within the genes coding for virulence factors. Within highly vaccinated populations, pertussis has reappeared (Mooi et al. 1998). Several virulence factors are controlled by the bvg locus, and experiments altering this locus, along with modulation of specific virulence factor expression, have illuminated the roles of virulence factors in promoting bacterial survival by immunomodulation (Mills 2001). See the table below for details.
Adapted from Mills 2001
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