Rickettsiae actively escape from vacuoles and replicate free in the cytoplasm of host cells, where inflammasomes survey the invading pathogens. In the present study, we investigated the interactions of Rickettsia australis with the inflammasome in both mouse and human macrophages. R. australis induced a significant level of IL-1β secretion by human macrophages, which was significantly reduced upon treatment with an inhibitor of caspase-1 compared to untreated controls, suggesting caspase-1-dependent inflammasome activation. Rickettsia induced significant secretion of IL-1β and IL-18 in vitro by infected mouse bone marrow-derived macrophages (BMMs) as early as 8–12 h post infection (p.i.) in a dose-dependent manner. Secretion of these cytokines was accompanied by cleavage of caspase-1 and was completely abrogated in BMMs deficient in caspase-1/caspase-11 or apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), suggesting that R. australis activate the ASC-dependent inflammasome. Interestingly, in response to the same quantity of rickettsiae, NLRP3-/- BMMs significantly reduced the secretion level of IL-1β compared to wild type (WT) controls, suggesting that NLRP3 inflammasome contributes to cytosolic recognition of R. australis in vitro. Rickettsial load in spleen, but not liver and lung, of R. australis-infected NLRP3-/- mice was significantly greater compared to WT mice. These data suggest that NLRP3 inflammasome plays a role in host control of bacteria in vivo in a tissue-specific manner. Taken together, our data, for the first time, illustrate the activation of ASC-dependent inflammasome by R. australis in macrophages in which NLRP3 is involved.
Rickettsiae can cause life-threatening infections in humans. Macrophages are one of the initial targets for rickettsiae after inoculation by ticks.
Chikungunya virus (CHIKV) is an arthritogenic alphavirus that during the last decade has significantly expanded its geographical range and caused large outbreaks of human disease around the world. Although mortality rates associated with CHIKV outbreaks are low, acute and chronic illnesses caused by CHIKV represent a significant burden of disease largely affecting low and middle income countries. This report summarizes the current status of vaccine development for CHIKV.
Spotted fever group rickettsiae cause potentially life-threatening infections throughout the world. Several members of the Tolllike receptor (TLR) family are involved in host response to rickettsiae, and yet the mechanisms by which these TLRs mediate host immunity remain incompletely understood. In the present study, we found that host susceptibility of MyD88 ؊/؊ mice to infection with Rickettsia conorii or Rickettsia australis was significantly greater than in wild-type (WT) mice, in association with severely impaired bacterial clearance in vivo. R. australis-infected MyD88 ؊/؊ mice showed significantly lower expression levels of gamma interferon (IFN-␥), interleukin-6 (IL-6), and IL-1, accompanied by significantly fewer inflammatory infiltrates of macrophages and neutrophils in infected tissues, than WT mice. The serum levels of IFN-␥, IL-12, IL-6, and granulocyte colonystimulating factor were significantly reduced, while monocyte chemoattractant protein 1, macrophage inflammatory protein 1␣, and RANTES were significantly increased in infected MyD88؊/؊ mice compared to WT mice. Strikingly, R. australis infection was incapable of promoting increased expression of MHC-II high and production of IL-12p40 in MyD88 ؊/؊ bone marrow-derived dendritic cells (BMDCs) compared to WT BMDCs, although costimulatory molecules were upregulated in both types of BMDCs. Furthermore, the secretion levels of IL-1 by Rickettsia-infected BMDCs and in the sera of infected mice were significantly reduced in MyD88 ؊/؊ mice compared to WT controls, suggesting that in vitro and in vivo production of IL-1 is MyD88 dependent. Taken together, our results suggest that MyD88 signaling mediates instructive signals in DCs and secretion of IL-1 and type 1 immune cytokines, which may account for the protective inflammatory response during rickettsial infection. R ickettsiae are obligately intracellular bacteria that cause potentially life-threatening diseases worldwide, with fatality rates as high as 30% if not treated promptly (1, 2). Currently, there is no available U.S. Food and Drug Administration-approved vaccine against rickettsial infections. Our previous studies employing mouse models have identified the critical role of gamma interferon (IFN-␥) and cytotoxic CD8 ϩ T cells in host clearance of rickettsiae in vivo (2). Increased inflammatory responses, such as the serum levels of IFN-␥, tumor necrosis factor alpha (TNF-␣), and interleukin-6 (IL-6), have been reported in both human mild and severe rickettsioses (3, 4). However, how rickettsiae initiate these inflammatory immune responses in vivo and the contribution of innate immune elements to host protection still remain elusive.The initial sensing of infection is mediated by innate pattern recognition receptors (PRRs), which mainly include Toll-like receptors (TLRs) and NOD-like receptors (5). Upon activation by microbes, TLRs transduce signals mostly via an adaptor molecule, MyD88 (6). In addition, activation of TLRs also recruits other adaptor proteins, including TIR domain-containi...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.