As described in our recently featured report, the anti-infectives market is poised to experience considerable growth in the next few years, with a forecast market value that is expected to double in size to more than $44 billion by 2010. One major problem related to infectious diseases is that of sepsis. Infection with group A streptococci causes a wide spectrum of disease including pharyngitis, necrotizing fascitis and septic (toxic) shock. Sepsis represents a particularly troubling problem accounting for high levels of mortality. This condition occurs in 1-2% of hospital admissions and is secondary to the appearance of bacterial toxins in the circulation. Sepsis is caused by a number of gram-negative organisms including E. coli, or meningococci and by gram-positive pathogens such as staphylococci and streptococci. Infection with group A streptococci causes a wide spectrum of disease including pharyngitis, necrotizing fasciitis and septic (toxic) shock. The frequent progression of sepsis to septic shock results in hypotension and inadequate tissue perfusion. Septic shock carries a 45% risk of mortality making it the most common cause of death in intensive care units. Consequently over 30 pharmaceutical products are in development for this condition although few have reached the market yet. Many of these target specific inflammatory mediators and have thus been, in general, unsuccessful since the process of sepsis involves multiple mediators. More successful strategies include the targeting of the end stage of sepsis, altered coagulation, and Eli Lilly's Xigris, which is effective in this respect, has the potential to become a blockbuster product. This approach also supports the concept of targeting host mediators rather than the pathogens themselves as a new infectious disease strategy.

The role of host mediators in infectious diseases has also lead to the idea that host genetic factors that regulate the release of these mediators confer predisposition or protection to infection. For example, although the release of inflammatory cytokines triggered by streptococcal toxins known as superantigens has a pivotal role in invasive streptococcal disease, individuals infected with the same strain can develop very different manifestations. This appears to be related to the cytokine response to superantigen. Investigating this concept further, Tennessee-based researchers have recently published data showing that specific HLA class II haplotypes conferred strong protection from severe systemic disease, whereas others increased the risk of severe disease. Patients with the DRB1(*)1501/DQB1(*)0602 haplotype mounted significantly reduced responses to infection and were less likely to develop severe systemic disease. In these resistant patients this was related to a reduced proliferative and cytokine response of peripheral blood mononuclear cells to superantigen. Interestingly, the influence that this haplotype had on the severity of necrotizing fasciitis was weaker. These data therefore suggest HLA II allelic variation contributes to differences in severity of invasive streptococcal infections through their ability to regulate cytokine responses triggered by streptococcal superantigens.

The response to (super)antigen depends on the formation of a binding complex involving the superantigen, the HLA II molecule and the T cell receptor. Several class II binding site blockers are in development for autoimmune disorders and neoplastic disease and it has been suggested that blocking superantigen-class II interactions may also limit the response to antigen. These immunogenetic data support this concept and further investigation of binding to and structural characteristics of class II binding in resistant patients with the DRB1(*)1501/DQB1(*)0602 haplotype may lead to the development of improved small molecule antagonists of superantigen binding and hence protection against septic shock. On the other hand these data may lead to effective pharmacogenomic approaches to infectious disease. The growing area of pharmacogenomics allows patients to be treated according to their particular genotype (click here to access our featured article on this field). In this instance patients with a haplotype that is related to a severe response to sepsis may be treated more aggressively and perhaps with a molecule that specifically targets that particular haplotype.

Entry date January, 2003

Adapted from Kotb et al, Nat Med 2002 Dec;8(12):1398-404 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.