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1.
PLoS One ; 16(6): e0253084, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34111210

RESUMO

Rickettsioses are neglected and emerging potentially fatal febrile diseases that are caused by obligate intracellular bacteria, rickettsiae. Rickettsia (R.) typhi and R. prowazekii constitute the typhus group (TG) of rickettsiae and are the causative agents of endemic and epidemic typhus, respectively. We recently generated a monoclonal antibody (BNI52) against R. typhi. Characterization of BNI52 revealed that it specifically recognizes TG rickettsiae but not the members of the spotted fever group (SFG) rickettsiae. We further show that BNI52 binds to protein fragments of ±30 kDa that are exposed on the bacterial surface and also present in the periplasmic space. These protein fragments apparently derive from the cytosolic GroEL protein of R. typhi and are also recognized by antibodies in the sera from patients and infected mice. Furthermore, BNI52 opsonizes the bacteria for the uptake by antigen presenting cells (APC), indicating a contribution of GroEL-specific antibodies to protective immunity. Finally, it is interesting that the GroEL protein belongs to 32 proteins that are differentially downregulated by R. typhi after passage through immunodeficient BALB/c CB17 SCID mice. This could be a hint that the rickettsia GroEL protein may have immunomodulatory properties as shown for the homologous protein from several other bacteria, too. Overall, the results of this study provide evidence that GroEL represents an immunodominant antigen of TG rickettsiae that is recognized by the humoral immune response against these pathogens and that may be interesting as a vaccine candidate. Apart from that, the BNI52 antibody represents a new tool for specific detection of TG rickettsiae in various diagnostic and experimental setups.


Assuntos
Anticorpos Monoclonais/metabolismo , Chaperonina 60/imunologia , Infecções por Rickettsia/sangue , Rickettsia typhi/imunologia , Animais , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/metabolismo , Anticorpos Monoclonais/sangue , Antígenos de Bactérias/imunologia , Linhagem Celular , Células HEK293 , Humanos , Camundongos Endogâmicos BALB C , Camundongos SCID , Periplasma/metabolismo , Infecções por Rickettsia/imunologia , Infecções por Rickettsia/microbiologia , Xenopus laevis
2.
PLoS Negl Trop Dis ; 11(2): e0005404, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28222146

RESUMO

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.


Assuntos
Citocinas/metabolismo , Rickettsia typhi/imunologia , Subpopulações de Linfócitos T/imunologia , Células Th1/imunologia , Células Th17/imunologia , Tifo Endêmico Transmitido por Pulgas/imunologia , Tifo Endêmico Transmitido por Pulgas/patologia , Transferência Adotiva , Animais , Modelos Animais de Doenças , Camundongos Endogâmicos BALB C , Camundongos SCID
3.
PLoS Negl Trop Dis ; 10(11): e0005089, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27875529

RESUMO

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.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Macrófagos/imunologia , Rickettsia typhi/imunologia , Tifo Endêmico Transmitido por Pulgas/imunologia , Transferência Adotiva , Animais , Linfócitos T CD4-Positivos/microbiologia , Linfócitos T CD8-Positivos/microbiologia , Feminino , Humanos , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Rickettsia typhi/fisiologia , Células Th1/imunologia , Células Th1/microbiologia , Tifo Endêmico Transmitido por Pulgas/microbiologia
4.
PLoS Negl Trop Dis ; 10(8): e0004935, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27548618

RESUMO

Rickettsia (R.) typhi is the causative agent of endemic typhus, an emerging febrile disease that is associated with complications such as pneumonia, encephalitis and liver dysfunction. To elucidate how innate immune mechanisms contribute to defense and pathology we here analyzed R. typhi infection of CB17 SCID mice that are congenic to BALB/c mice but lack adaptive immunity. CB17 SCID mice succumbed to R. typhi infection within 21 days and showed high bacterial load in spleen, brain, lung, and liver. Most evident pathological changes in R. typhi-infected CB17 SCID mice were massive liver necrosis and splenomegaly due to the disproportionate accumulation of neutrophils and macrophages (MΦ). Both neutrophils and MΦ infiltrated the liver and harbored R. typhi. Both cell populations expressed iNOS and produced reactive oxygen species (ROS) and, thus, exhibited an inflammatory and bactericidal phenotype. Surprisingly, depletion of neutrophils completely prevented liver necrosis but neither altered bacterial load nor protected CB17 SCID mice from death. Furthermore, the absence of neutrophils had no impact on the overwhelming systemic inflammatory response in these mice. This response was predominantly driven by activated MΦ and NK cells both of which expressed IFNγ and is considered as the reason of death. Finally, we observed that iNOS expression by MΦ and neutrophils did not correlate with R. typhi uptake in vivo. Moreover, we demonstrate that MΦ hardly respond to R. typhi in vitro. These findings indicate that R. typhi enters MΦ and also neutrophils unrecognized and that activation of these cells is mediated by other mechanisms in the context of tissue damage in vivo.


Assuntos
Inflamação/imunologia , Inflamação/patologia , Células Matadoras Naturais/imunologia , Fígado/patologia , Macrófagos/imunologia , Neutrófilos/imunologia , Tifo Endêmico Transmitido por Pulgas/imunologia , Animais , Encéfalo/microbiologia , Citocinas/biossíntese , Modelos Animais de Doenças , Imunidade Inata , Inflamação/sangue , Inflamação/microbiologia , Interferon gama/biossíntese , Fígado/microbiologia , Pulmão/microbiologia , Ativação de Macrófagos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Necrose , Óxido Nítrico Sintase Tipo II/biossíntese , Espécies Reativas de Oxigênio/metabolismo , Rickettsia typhi/imunologia , Rickettsia typhi/patogenicidade , Baço/microbiologia , Baço/patologia , Tifo Endêmico Transmitido por Pulgas/microbiologia , Tifo Endêmico Transmitido por Pulgas/patologia
5.
Infect Immun ; 84(5): 1615-1632, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26975992

RESUMO

Rickettsioses are emerging febrile diseases caused by obligate intracellular bacteria belonging to the family Rickettsiaceae. Rickettsia typhi belongs to the typhus group (TG) of this family and is the causative agent of endemic typhus, a disease that can be fatal. In the present study, we analyzed the course of R. typhi infection in C57BL/6 RAG1(-/-) mice. Although these mice lack adaptive immunity, they developed only mild and temporary symptoms of disease and survived R. typhi infection for a long period of time. To our surprise, 3 to 4 months after infection, C57BL/6 RAG1(-/-) mice suddenly developed lethal neurological disorders. Analysis of these mice at the time of death revealed high bacterial loads, predominantly in the brain. This was accompanied by a massive expansion of microglia and by neuronal cell death. Furthermore, high numbers of infiltrating CD11b(+) macrophages were detectable in the brain. In contrast to the microglia, these cells harbored R. typhi and showed an inflammatory phenotype, as indicated by inducible nitric oxide synthase (iNOS) expression, which was not observed in the periphery. Having shown that R. typhi persists in immunocompromised mice, we finally asked whether the bacteria are also able to persist in resistant C57BL/6 and BALB/c wild-type mice. Indeed, R. typhi could be recultivated from lung, spleen, and brain tissues from both strains even up to 1 year after infection. This is the first report demonstrating persistence and reappearance of R. typhi, mainly restricted to the central nervous system in immunocompromised mice.


Assuntos
Infecções do Sistema Nervoso Central/microbiologia , Infecções do Sistema Nervoso Central/patologia , Inflamação/patologia , Rickettsia typhi/isolamento & purificação , Tifo Endêmico Transmitido por Pulgas/microbiologia , Tifo Endêmico Transmitido por Pulgas/patologia , Animais , Encéfalo/parasitologia , Encéfalo/patologia , Doença Crônica , Proteínas de Homeodomínio/genética , Pulmão/parasitologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase Tipo II/análise , Baço/parasitologia
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