MyD88 Is Required for Efficient Control of Coxiella burnetii Infection and Dissemination

Abstract

The intracellular pathogen Coxiella (C.) burnetii causes Q fever, a usually self-limiting respiratory infection that becomes chronic and severe in some patients. Innate immune recognition of C. burnetii and its role in the decision between resolution and chronicity is not understood well. However, TLR2 is important for the response to C. burnetii in mice, and genetic polymorphisms in Myd88 have been associated with chronic Q fever in humans. Here, we have employed MyD88-deficient mice in infection models with the attenuated C. burnetii Nine Mile phase II strain (NMII). Myd88−/− macrophages failed to restrict the growth of NMII in vitro, and to upregulate production of the cytokines TNF, IL-6, and IL-10. Following intraperitoneal infection, NMII bacterial burden was significantly higher on day 5 and 20 in organs of Myd88−/− mice. After infection via the natural route by intratracheal injection, a higher bacterial load in the lung and increased dissemination of NMII to other organs was observed in MyD88-deficient mice. While wild-type mice essentially cleared NMII on day 27 after intratracheal infection, it was still readily detectable on day 42 in multiple organs in the absence of MyD88. Despite the elevated bacterial load, Myd88−/− mice had less granulomatous inflammation and expressed significantly lower levels of chemoattractants, inflammatory cytokines, and of several IFNγ-induced genes relevant for control of intracellular pathogens. Together, our results show that MyD88-dependent signaling is essential for early control of C. burnetii replication and to prevent systemic spreading. The continued presence of NMII in the organs of Myd88−/− mice constitutes a new mouse model to study determinants of chronicity and resolution in Q fever.

Pattern Recognition Receptors in Innate Immunity to Obligate Intracellular Bacteria

“…A separate study has revealed similar findings, showing that MyD88 −/− MΦs bear significantly higher bacterial loads at 72 hpi than WT controls, as well as diminished production of IL-6 and IL-10. Together, these results indicate a role of MyD88 in producing both a cytokine response and regulating the bacterial load in MΦs [136]. In that study, after intratracheal infection, the bacterial load of C. burnetii NMII was consistently higher in the lung, spleen, heart, and liver tissues from 7 to 120 dpi; in contrast, MyD88 +/− mice showed complete clearance at 27 dpi [136].…”

“…Vacuole TLR2 [111,113] Myd88 [112] TLR7 [111] TLR9 [114] NOD2 [113] Coxiella burnetii MyD88 [135][136][137] TLR1 [135] TRIF [137] TLR2 [137,138] Myd88, TRIF [137] TLR4 [137] *Denotes primary mode of transmission.…”

“…Studies using animal models of Q fever have shed light on the roles of TLRs in the pathogenesis of infection. Multiple reports have shown that TLR2/4 and MyD88-mediated signaling is essential in controlling the replication of C. burnetii Nine Mile Phase II (NMII) infection in vitro and in vivo [136][137][138]. An early report using CHO cells transfected with functional TLR2 or TLR4 has revealed that C. burnetii NMII activates only TLR2 + cells [138].…”

Screening of immune-related differentially expressed genes from primary lymphatic organs of broilers fed with probiotic bacillus cereus PAS38 based on suppression subtractive hybridization

“…Among them, IL-1B, IL-2 and IL-6 are all common interleukins, they play an important role in lymphocytes activation, production of cytokines, antibodies and complement [40][41][42]. And MYD88, IRF1 and TLR4, play key roles in pathogen recognition, activation and conduction of immune signals [43][44][45].…”

T-Bet Controls Susceptibility of Mice to Coxiella burnetii Infection

“…This latter program is characterized by the low production of inflammatory cytokines and the overproduction of immunoregulatory cytokines, such as interleukin (IL)-10, which is associated with persistent infection in tissues from mice overexpressing IL-10 ( Meghari et al, 2008 ) and persistent Q fever in humans ( Honstettre et al, 2003 ). More recently, in intraperitoneal or intratracheal infection of Myd88 –/– mice, persistence of C. burnetii has been observed in organs with less granulomatous inflammation and decreased expression of several genes involved in the intracellular control of bacteria ( Kohl et al, 2019 ). C. burnetii also affects the functions of the dendritic cells (DCs).…”