CD4+ T Cells Are as Protective as CD8+ T Cells against Rickettsia typhi Infection by Activating Macrophage Bactericidal Activity.

Kristin Moderzynski,Ulricke Richardt,Jessica Rauch,Bernhard Fleischer,Svenja Kuehl,Liza Heine,Stefanie Papp,Anke Osterloh,Maya Williams

doi:10.1371/journal.pntd.0005089

Abstract

Rickettsia typhi is an intracellular bacterium that causes endemic typhus, a febrile disease that can be fatal due to complications including pneumonia, hepatitis and meningoencephalitis, the latter being a regular outcome in T and B cell-deficient C57BL/6 RAG1-/- mice upon Rickettsia typhi infection. Here, we show that CD4+ TH1 cells that are generated in C57BL/6 mice upon R. typhi infection are as protective as cytotoxic CD8+ T cells. CD4+- as well as CD8+-deficient C57BL/6 survived the infection without showing symptoms of disease at any point in time. Moreover, adoptively transferred CD8+ and CD4+ immune T cells entered the CNS of C57BL/6 RAG1-/- mice with advanced infection and both eradicated the bacteria. However, immune CD4+ T cells protected only approximately 60% of the animals from death. They induced the expression of iNOS in infiltrating macrophages as well as in resident microglia in the CNS which can contribute to bacterial killing but also accelerate pathology. In vitro immune CD4+ T cells inhibited bacterial growth in infected macrophages which was in part mediated by the release of IFNγ. Collectively, our data demonstrate that CD4+ T cells are as protective as CD8+ T cells against R. typhi, provided that CD4+ TH1 effector cells are present in time to support bactericidal activity of phagocytes via the release of IFNγ and other factors. With regard to vaccination against TG Rickettsiae, our findings suggest that the induction of CD4+ TH1 effector cells is sufficient for protection.

Highlights

Rickettsiae (R.) are small obligate intracellular bacteria that are transmitted to humans by arthropod vectors
Endemic typhus caused by Rickettsia typhi usually is a relatively mild disease
CNS inflammation and neurological symptoms are complications that can occur in severe cases. This outcome of disease is regularly observed in T and B cell-deficient C57BL/6 RAG1-/- mice upon infection with R. typhi

Summary

Introduction

Rickettsiae (R.) are small obligate intracellular bacteria that are transmitted to humans by arthropod vectors. R. prowazekii and R. typhi represent the two members of the typhus group (TG) of Rickettsiae [1, 2] and are the causative agents of epidemic and endemic typhus, respectively. Both diseases appear with similar symptoms including high fever, headache, myalgia and joint pain, nausea and vomiting. Neurological symptoms such as confusion and stupor are common [3]. As clinical presentations are often non-specific, endemic typhus, is clearly underdiagnosed and, often unrecognized [3, 9]

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Conclusion