Establishment of a Rhesus Macaque Model for Scrub Typhus Transmission: Pilot Study to Evaluate the Minimal Orientia tsutsugamushi Transmission Time by Leptotrombidium chiangraiensis Chiggers

Linsuwanon, Piyada; Wongwairot, Sirima; Auysawasdi, Nutthanun; Monkanna, Taweesak; Richards, Allen L.; Leepitakrat, Surachai; Sunyakumthorn, Piyanate; Im-Erbsin, Rawiwan; Poole-Smith, Katie; McCardle, Patrick W.

doi:10.3390/pathogens10081028

“…G-CSF is a growth factor that stimulates the bone marrow to produce granulocytes, such as neutrophils and release them into the bloodstream [59]. Increased G-CSF levels in the blood have been reported in a rhesus macaque model of scrub typhus [60]. Our recent study revealed that virulent Karp infection can induce higher levels of G-CSF than the less virulent Gilliam infection [18], indicating that G-CSF might be related to the hyperinflammation and immunopathology.…”

Section: Plos Pathogensmentioning

confidence: 88%

Lack of the IFN-γ signal leads to lethal Orientia tsutsugamushi infection in mice with skin eschar lesions

Liang,

Wang,

Sun

et al. 2024

PLoS Pathog

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Scrub typhus is an acute febrile disease due to Orientia tsutsugamushi (Ot) infection and can be life-threatening with organ failure, hemorrhage, and fatality. Yet, little is known as to how the host reacts to Ot bacteria at early stages of infection; no reports have addressed the functional roles of type I versus type II interferon (IFN) responses in scrub typhus. In this study, we used comprehensive intradermal (i.d.) inoculation models and two clinically predominant Ot strains (Karp and Gilliam) to uncover early immune events. Karp infection induced sequential expression of Ifnb and Ifng in inflamed skin and draining lymph nodes at days 1 and 3 post-infection. Using double Ifnar1-/-Ifngr1-/- and Stat1-/- mice, we found that deficiency in IFN/STAT1 signaling resulted in lethal infection with profound pathology and skin eschar lesions, which resembled to human scrub typhus. Further analyses demonstrated that deficiency in IFN-γ, but not IFN-I, resulted in impaired NK cell and macrophage activation and uncontrolled bacterial growth and dissemination, leading to metabolic dysregulation, excessive inflammatory cell infiltration, and exacerbated tissue damage. NK cells were found to be the major cellular source of innate IFN-γ, contributing to the initial Ot control in the draining lymph nodes. In vitro studies with dendritic cell cultures revealed a superior antibacterial effect offered by IFN-γ than IFN-β. Comparative in vivo studies with Karp- and Gilliam-infection revealed a crucial role of IFN-γ signaling in protection against progression of eschar lesions and Ot infection lethality. Additionally, our i.d. mouse models of lethal infection with eschar lesions are promising tools for immunological study and vaccine development for scrub typhus.

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“…G-CSF is a growth factor that stimulates the bone marrow to produce granulocytes, such as neutrophils and release them into the bloodstream[55]. Increased G-CSF levels in the blood have been reported in a rhesus macaque model of scrub typhus[56]. Our recent study revealed that virulent Karp infection can induce higher levels of G- CSF than the less virulent Gilliam infection[18], indicating that G-CSF might be related to the hyperinflammation and immunopathology.…”

Section: Discussionmentioning

confidence: 99%

Lack of the IFN-γ signal leads to lethalOrientia tsutsugamushiinfection in mice with skin eschar lesions

Liang,

Wang,

Sun

et al. 2024

Preprint

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Scrub typhus is an acute febrile disease due toOrientia tsutsugamushi(Ot) infection and can be life-threatening with organ failure, hemorrhage, and fatality. Yet, little is known as to how the host reacts toOtbacteria at early stages of infection; no reports have addressed the functional roles of type I versus type II interferon (IFN) responses in scrub typhus. In this study, we used comprehensive intradermal (i.d.) inoculation models and two clinically predominantOtstrains (Karp and Gilliam) to uncover early immune events. Karp infection induced sequential expression ofIfnbandIfngin inflamed skin and draining lymph nodes at days 1 and 3 post-infection. Using doubleIfnar1-/-Ifngr1-/-andStat1-/-mice, we found that deficiency in IFN/STAT1 signaling resulted in lethal infection with profound pathology and skin eschar lesions, that resembled to human scrub typhus. Further analyses demonstrated that deficiency in IFN-γ, but not IFN-I, resulted in impaired NK cell and macrophage activation and uncontrolled bacterial growth and dissemination, leading to metabolic dysregulation, excessive inflammatory cell infiltration, and exacerbated tissue damage. NK cells were found to be the major cellular source of early IFN-γ, contributing to the initialOtcontrol. In vitro studies with dendritic cell cultures revealed a superior antibacterial effect offered by IFN-γ than IFN-β. Comparative in vivo studies with Karp- and Gilliam-infection revealed a crucial role of IFN-γ signaling in protection against progression of eschar lesions andOtinfection lethality. Additionally, our i.d. mouse models of lethal infection with eschar lesions are promising tools for immunological study and vaccine development for scrub typhus.SummaryScrub typhus can lead to severe complications and even fatality if not treated properly; however, the early host immune responses toOtbacterium infection remain unclear. This study focused on the functional roles of IFNs in i.d. inoculation mouse models of scrub typhus. We found that mice lacking IFN receptors were highly susceptible toOtinfection, which resulted in severe pathology and skin eschar lesions that resembled to human scrub typhus. Further investigation revealed that the lack of IFN-γ, but not IFN-I, resulted in dysregulated innate immune responses, leading to uncontrolled bacterial burdens and tissue damage. Using IFN-γ reporter mice and neutralizing antibody treatment, we confirmed that NK cells were the major source of early IFN-γ, and thus played a key role in controllingOtdissemination. Moreover, our comparative studies with twoOtstrains revealed bacterium strain- and dose-dependent eschar formation and disease severity. In conclusion, our study highlights the crucial role of IFN-γ signaling in ensuring host protection againstOtinfection. Our mouse models resemble skin eschar lesions and lethal infections observed in human disease, offering potential for future immunological studies on scrub typhus.

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“…Rhesus monkeys (Macaca mulatta) are the most common NHP used in biomedical research [4]. Recently, this NHP species has been used especially as a model for COVID-19 [5] and scrub typhus transmission studies [6].…”

Section: Introductionmentioning

confidence: 99%

First Report of ‘Candidatus Mycoplasma haematomacacae’ in Laboratory-Kept Rhesus Monkeys (Macaca mulatta) Maintained in Rio de Janeiro, Brazil

Mongruel

¹

,

Somma

²

,

Pinto

³

et al. 2022

Veterinary Sciences

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Health monitoring programs in animals used as experimental models are essential, since only disease-free subjects are considered suitable for research purposes. In laboratory-kept animals, hemoplasmas have been described as an important confounding variable. Different hemoplasma species have been detected infecting non-human primates (NHP) from Brazil. However, the occurrence of hemoplasma species in laboratory-kept NHP in Brazil has not-yet been assessed. Accordingly, this study aimed (i) to screen laboratory-kept rhesus monkeys for hemoplasmas, (ii) to verify if any of the hemoplasma-positive animals demonstrate hematological abnormalities, and (iii) to assess the genotype diversity of hemoplasma species in NHP from Brazil. Five out of eight (62.5%; 95% CI: 3.05–8.63) rhesus monkeys tested positive for hemotropic Mycoplasma spp. by PCR. Sequencing, phylogenetic, distance, and genotype diversity analyses of partial 16S rRNA gene demonstrate that rhesus monkeys were infected by ‘Candidatus Mycoplasma haematomacacae’ (formerly ‘Candidatus Mycoplasma haemomacaque’). Assessments of partial 16S rRNA diversity of hemoplasma species in NHP suggest that at least four genetically diverse groups may occur in Brazil. Although no hematological abnormalities were demonstrated in rhesus monkeys evaluated herein, future studies are needed to elucidate the influence of ‘Ca. M. haematomacacae’ as a confounding variable on research studies.

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Establishment of a Rhesus Macaque Model for Scrub Typhus Transmission: Pilot Study to Evaluate the Minimal Orientia tsutsugamushi Transmission Time by Leptotrombidium chiangraiensis Chiggers

Cited by 3 publications

References 59 publications

Lack of the IFN-γ signal leads to lethal Orientia tsutsugamushi infection in mice with skin eschar lesions

Lack of the IFN-γ signal leads to lethal Orientia tsutsugamushi infection in mice with skin eschar lesions

Lack of the IFN-γ signal leads to lethalOrientia tsutsugamushiinfection in mice with skin eschar lesions

First Report of ‘Candidatus Mycoplasma haematomacacae’ in Laboratory-Kept Rhesus Monkeys (Macaca mulatta) Maintained in Rio de Janeiro, Brazil

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