T Cells Mediate Cross‐Protective Immunity between Spotted Fever Group Rickettsiae and Typhus Group Rickettsiae

Valbuena, Gustavo; Jordan, Jeffrey M.; Walker, David H.

doi:10.1086/423819

Cited by 32 publications

(23 citation statements)

References 28 publications

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“…Cytotoxic activity of CD8 ϩ T cells, together with IFN-␥ production, has been demonstrated to be essential for protection against SFG rickettsiae (22)(23)(24)(25). Moreover, T cells have been shown to confer cross-protection between SFG and TG rickettsiae in susceptible C3H/HeN mice (87). In line with these observations, immunocompetent C57BL/6 wild-type mice are capable of controlling R. typhi.…”

Section: Discussionmentioning

confidence: 81%

Persisting Rickettsia typhi Causes Fatal Central Nervous System Inflammation

et al. 2016

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bRickettsioses 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.

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Section: Discussionmentioning

confidence: 81%

Persisting Rickettsia typhi Causes Fatal Central Nervous System Inflammation

et al. 2016

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“…This was evaluated only recently with 'Candidatus R. amblyommii' North Texas isolate, but it has been studied further in other species to understand protective immune responses and possible candidates for vaccine development (Feng and Waner, 1980;Walker et al, 1984;Feng and Walker, 2003;Valbuena et al, 2004;Blanton et al, 2014). All guinea pigs that had been infected previously with 'Candidatus R. amblyommii' survived developing transient disease after inoculation of R. rickettsii, while animals infected only with R. rickettsii showed all clinical signs and organ damage that is characteristic of severe disease (Walker et al, 1977;Walker and Henderson, 1978;Arguello et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, stimulation through the intracellular route that activates T cells and induces cytokines like IFN-␥, TNF-␣, IL-1B, and CCL5 seem to be important in eliminating pathogenic rickettsiae (Feng and Walker, 2000;Valbuena et al, 2004;Sahni et al, 2013). Infection with R. rickettsii probably occurred in guinea pigs previously infected with 'Candidatus R. amblyommii', given transient temperature increase, antibody production, and visible orchitis (one animal), but the resulting immune response efficiently eliminated R. rickettsii to levels undetectable by PCR.…”

Section: Discussionmentioning

confidence: 99%

Pathogenic potential of a Costa Rican strain of ‘Candidatus Rickettsia amblyommii’ in guinea pigs (Cavia porcellus) and protective immunity against Rickettsia rickettsii

Rivas

Moreira-Soto

Alvarado

et al. 2015

Ticks and Tick-borne Diseases

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'Candidatus Rickettsia amblyommii' is a spotted fever group rickettsia that is not considered pathogenic, although there is serologic evidence of possible infection in animals and humans. The aim of this study was to evaluate the pathogenic potential of a Costa Rican strain of 'Candidatus R. amblyommii' in guinea pigs and determine its capacity to generate protective immunity against a subsequent infection with a local strain of Rickettsia rickettsii isolated from a human case. Six guinea pigs were inoculated with 'Candidatus R. amblyommii' strain 9-CC-3-1 and two controls with cell culture medium. Health status was evaluated, and necropsies were executed at days 2, 4, and 13. Blood and tissues were processed by PCR to detect the gltA gene, and end titers of anti-'Candidatus R. amblyommii' IgG were determined by indirect immunofluorescence. To evaluate protective immunity, another 5 guinea pigs were infected with 'Candidatus R. amblyommii' (IGPs). After 4 weeks, these 5 IGPs and 3 controls (CGPs) were inoculated with pathogenic R. rickettsii. Clinical signs and titers of anti-Rickettsia IgG were determined. IgG titers reached 1:512 at day 13 post-infection with 'Candidatus R. amblyommii'. On day 2 after inoculation, two guinea pigs had enlarged testicles and 'Candidatus R. amblyommii' DNA was detected in testicles. Histopathology confirmed piogranulomatous orchitis with perivascular inflammatory infiltrate in the epididymis. In the protective immunity assay, anti-Rickettsia IgG end titers after R. rickettsii infection were lower in IGPs than in CGPs. IGPs exhibited only transient fever, while CGP showed signs of severe disease and mortality. R. rickettsii was detected in testicles and blood of CGPs. Results show that the strain 9-CC-3-1 of 'Candidatus R. amblyommii' was able to generate pathology and an antibody response in guinea pigs. Moreover, its capacity to generate protective immunity against R. rickettsii may modulate the epidemiology and severity of Rocky Mountain spotted fever in areas where both species circulate.

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“…These cells are critical effectors of immunity against rickettsial infections in mouse models that closely mimic the pathophysiology of severe human rickettsioses [18]; mice that survive a rickettsial infection with low numbers of rickettsiae become solidly immune against subsequent lethal challenge [10, 11]. These data and the difficulty of obtaining human samples due to diagnostic limitations and underreporting justify the use of the mouse models for the definition and validation of potential correlates of protection for vaccine testing.…”

Section: Discussionmentioning

confidence: 99%

“…Although antibodies were identified as the protective mechanism and correlate of protection in prior killed Rickettsia vaccines [4–8], it is also known that antibodies do not play a role in recovery from a primary infection [9], and that they are not cross-protective among phylogenetically distant rickettsiae [10]. In contrast, T cells can mediate cross-protection between rickettsiae as distantly related as R. typhi and R. conorii [11], suggesting that a T cell-mediated mechanism is partly responsible for the induction of long lasting cross-protective immunity and that T cell antigens should be included in the next generation of anti-rickettsial vaccines. To achieve this goal, the identification and validation of correlates of protective cellular immunity against rickettsial infections is a critical step that has yet to be addressed, and a particular focus on CD8 + T cells is necessary since their critical role over CD4 + T cells in resistance to rickettsial infections has been experimentally demonstrated [12,13].…”

Section: Introductionmentioning

confidence: 99%

Phenotype of the anti-Rickettsia CD8+ T cell response suggests cellular correlates of protection for the assessment of novel antigens

Caro-Gómez

Gaži

Cespedes

et al. 2014

Vaccine

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The obligately intracellular bacteria Rickettsia infect endothelial cells and cause systemic febrile diseases that are potentially lethal. No vaccines are currently available and current knowledge of the effective immune response is limited. Natural and experimental rickettsial infections provide strong and cross-protective cellular immunity if the infected individual survives the acute infection. Although resistance to rickettsial infections is attributed to the induction of antigen-specific T cells, particularly CD8+ T cells, the identification and validation of correlates of protective cellular immunity against rickettsial infections, an important step towards vaccine validation, remains a gap in this field. Here, we show that after a primary challenge with Rickettsia typhi in the C3H mouse model, the peak of anti-Rickettsia CD8+ T cell-mediated responses occurs 7 days post-infection (dpi), which coincides with the beginning of rickettsial clearance. At this time point, both effector-type and memory-type CD8+ T cells are present, suggesting that 7 dpi is a valid time point for the assessment of CD8+ T cell responses of mice previously immunized with protective antigens. Based on our results, we suggest four correlates of cellular protection for the assessment of protective rickettsial antigens: 1) production of IFN-γ by antigen experienced CD3+CD8+CD44high cells, 2) production of Granzyme B by CD27lowCD43low antigen-experienced CD8+ T cells, 3) generation of memory-type CD8+ T cells [Memory Precursor Effector Cells (MPECs), as well as CD127highCD43low, and CD27highCD43low CD8+ T cells], and 4) generation of effector-like memory CD8+ T cells (CD27lowCD43low). We propose that these correlates could be useful for the general assessment of the quality of the CD8+ T cell immune response induced by novel antigens with potential use in a vaccine against Rickettsia.

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T Cells Mediate Cross‐Protective Immunity between Spotted Fever Group Rickettsiae and Typhus Group Rickettsiae

Cited by 32 publications

References 28 publications

Persisting Rickettsia typhi Causes Fatal Central Nervous System Inflammation

Persisting Rickettsia typhi Causes Fatal Central Nervous System Inflammation

Pathogenic potential of a Costa Rican strain of ‘Candidatus Rickettsia amblyommii’ in guinea pigs (Cavia porcellus) and protective immunity against Rickettsia rickettsii

Phenotype of the anti-Rickettsia CD8+ T cell response suggests cellular correlates of protection for the assessment of novel antigens

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