Cytotoxic effector functions of T cells are not required for protective immunity against fatal Rickettsia typhi infection in a murine model of infection: Role of TH1 and TH17 cytokines in protection and pathology

Abstract

Endemic typhus caused by Rickettsia (R.) typhi is an emerging febrile disease that can be fatal due to multiple organ pathology. Here we analyzed the requirements for protection against R. typhi by T cells in the CB17 SCID model of infection. BALB/c wild-type mice generate CD4+ TH1 and cytotoxic CD8+ T cells both of which are sporadically reactivated in persistent infection. Either adoptively transferred CD8+ or CD4+ T cells protected R. typhi-infected CB17 SCID mice from death and provided long-term control. CD8+ T cells lacking either IFNγ or Perforin were still protective, demonstrating that the cytotoxic function of CD8+ T cells is not essential for protection. Immune wild-type CD4+ T cells produced high amounts of IFNγ, induced the release of nitric oxide in R. typhi-infected macrophages and inhibited bacterial growth in vitro via IFNγ and TNFα. However, adoptive transfer of CD4+IFNγ-/- T cells still protected 30–90% of R. typhi-infected CB17 SCID mice. These cells acquired a TH17 phenotype, producing high amounts of IL-17A and IL-22 in addition to TNFα, and inhibited bacterial growth in vitro. Surprisingly, the neutralization of either TNFα or IL-17A in CD4+IFNγ-/- T cell recipient mice did not alter bacterial elimination by these cells in vivo, led to faster recovery and enhanced survival compared to isotype-treated animals. Thus, collectively these data show that although CD4+ TH1 cells are clearly efficient in protection against R. typhi, CD4+ TH17 cells are similarly protective if the harmful effects of combined production of TNFα and IL-17A can be inhibited.

Immune response against rickettsiae: lessons from murine infection models

“…TNFα also induces the expression of iNOS in MΦ [ 87 ] and synergizes with IFNγ in this effect [ 71 ]. IFNγ has been shown to inhibit the growth of R. prowazekii in murine and human fibroblasts [ 90 ], and IFNγ as well as TNFα inhibit the growth of R. typhi in murine MΦ in vitro [ 45 ]. IFNγ and TNFα as well as IL-1β and RANTES also activate bacterial killing of R. conorii in human THP1 MΦ, AKN-1 hepatocytes and HUVEC ECs via NO-dependent mechanisms [ 91 ].…”

“… − Mild hepatitis [ 44 ] CB17 SCID R. conorii i.v. − Mild hepatitis [ 44 ] R. typhi s.c. ++++ Strong hepatitis, splenomegaly, systemic inflammation (IFNγ) [ 40 , 45 ] RAG2 −/− R. typhi s.c. ++++ Strong hepatitis, splenomegaly, systemic inflammation (IFNγ) [ 45 ] IFNγ −/− R. typhi s.c. − [ 45 ] Perforin −/− R. typhi s.c. − [ 45 ] C57BL/6 Wild-type R. australis i.v. + [ 46 ] R. akari i.p.…”

IL‐17 and IL‐22 elicited by a DNA vaccine encoding ROP13 associated with protection againstToxoplasma gondiiin BALB/c mice

“…There is evidence indicating that IL-22 has antiparasitic effects during infection with the intracellular parasite, Eimeria falciformis that belongs to the same phylum with T. gondii (Stange et al, 2012). In contrast with these findings, IL-22 but not IL-17 is shown to drive inflammation and tissue injury following mice infection with T. gondii (Muñoz et al, 2009 (Moderzynski et al, 2017). This compliments recent novel findings that Th17 cells provide stronger protection, compared with Th1 responses, against the intracellular microorganism T. cruzi (Cai et al, 2016).…”

“…Furthermore, recently published data from a mouse model of rickettsial infection, an obligate intracellular bacterium, demonstrates that either Th1 or Th17 responses can have protective effects. Surprisingly cells producing IL‐17A or IL‐22 are as protective as IFN‐γ producing Th1 cells, if the immunopathologic effects of TNF‐α are controlled (Moderzynski et al, ). This compliments recent novel findings that Th17 cells provide stronger protection, compared with Th1 responses, against the intracellular microorganism T .…”

Importancia de las proteínas OmpA y OmpB en el desarrollo de vacunas contra la rickettsiosis

“…Estas proteínas son autotrasportadores de distintos pesos y así, OmpA tiene un tamaño aproximado entre 135 y 247 kDa, en tanto la OmpB oscila entre 120-168 kDa. Ambas son factores de virulencia de la bacteria debido a blanco para los linfocitos T citotóxicos, para lo cual es necesaria la presencia de IFN-γ y TNF-α para inducir la actividad bactericida y junto a esto también, se activen los macrófagos, que son los que tienen más impacto en la respuesta inmune celular (35)(36)(37)(38)(39).…”