Pathogenesis and immunotherapy of streptococcal septicemia and shock

Streptococei have been recognized as important causes of severe sepsis. Increased frequencies of streptococcal toxic shock syndrome caused by group A streptococcus (GAS) have been noted worldwide during the last 15 years. More over the incidence of viridans streptococcal and group B streptococcal (GBS) sepsis in immunocompromised individuals has increased during this time period.

The vast majority of outbreaks of invasive GAS infections have been caused by GAS strains of serotype M1T1. In order to determine whether distinct subtypes of these strains were responsible for the more severe manifestations, we examined 35 M1T1 strains obtained from severe or non-severe cases with respect to genetic diversity, superantigen expression, mitogenic and cytokine-inducing capacity. The study showed that highly related M1T1 strains, some indistinguishable, could cause disease of starkly varying severity. This finding underscores the importance of host factors in the pathogenesis of invasive GAS infections.

Superantigen-induced cytokine responses have been shown to be of major importance in the pathogenesis of invasive GAS infections. Here we investigated whether varying clinical manifestations of either viridans streptococcal sepsis in neutropenic patients or serotype V GB S sepsis were related to differences between isolates in their capacity to induce proinflammatory responses. Analyses of cytokine responses elicited by culture supernatants as well as heat-killed bacteria revealed a massive induction of pro-inflammatory cytokines. In contrast to GAS, viridans streptococcal or GBS isolates did not induce any T cell proliferation and no production of the T cell cytokines TNFbeta or IFN-gamma could be demonstrated, indicating that these strains did not produce any superantigenic activity. Heat-killed viridans streptococcal and GBS isolates induced a cytokine production profile that closely resembled that of the gram-negative endotoxin with an early potent induction of IL1beta, IL8 and TNFalpha. Culture supernatants prepared from GBS isolates differed from those prepared from GAS and viridans streptococcus since no induction of IL1beta could be demonstrated. Hence, GBS seems to induce a cytokine induction profile, which is distinct from other streptococci. Importantly, no difference in cytokine-inducing capacity could be found between cohorts of isolates from severe and non-severe cases. These findings underscore the importance of both host and bacterial factors, contributing to the inflammatory response and consequently progression of disease.

Intravenous polyspecific immunoglobulin (Ig) G has been suggested to be an efficient adjunctive therapy for invasive GAS diseases mainly due to its ability to neutralize a wide variety of superantigens, and down-regulate pro-inflammatory cytokine responses. We extended these analyses to determine the relative neutralizing activity in polyspecific IgG, IgM, and IgA preparations against GAS superantigens. The study showed that IgM and IgA were potent inhibitors of specific streptococcal superantigens, and the most efficient neutralization of the superantigen SpeA was achieved by an Ig-preparation containing all three isotypes. These findings may have implications for the optimization of immunoglobulin therapy in invasive streptococcal infections.

This thesis emphasizes the importance of host-pathogen interactions in deter~ the degree of inflammation and therefore the outcome of disease. Although, there are similarities in cytokine responses to GAS, GBS, and viridans streptococcus, they all have unique cytokine induction profiles.

List of scientific papers

I. Chatellier S, Ihendyane N, Kansal RG, Khambaty F, Basma H, Norrby-Teglund A, Low DE, McGeer A, Kotb M (2000). Genetic relatedness and superantigen expression in group A streptococcus serotype M1 isolates from patients with severe and nonsevere invasive diseases. Infect Immun. 68(6): 3523-34.
https://pubmed.ncbi.nlm.nih.gov/10816507

II. Ihendyane N, Sparrelid E, Wretlind B, Remberger M, Andersson J, Ljungman P, Ringden O, Henriques Normark B, Allen U, Low DE, Norrby-Teglund A (2003). Viridans streptococcal septicaemia in neuropenic patients: role of pro-inflammatory cytokines. Bone Marrow Transplantation.

III. Ihendyane N, Low DE, Norgren M, Sellin M, Persson E, Norrby-Teglund A (2003). Invasive and non-invasive serotype V group B streptococcal isolates are potent inducers of pro-inflammatory cytokine responses. [Manuscript]

IV. Norrby-Teglund A, Ihendyane N, Kansal R, Basma H, Kotb M, Andersson J, Hammarstrom L (2000). Relative neutralizing activity in polyspecific IgM, IgA, and IgG preparations against group A streptococcal superantigens. Clin Infect Dis. 31(5): 1175-82. Epub 2000 Nov 10
https://pubmed.ncbi.nlm.nih.gov/11073749