The Obligate Intracellular Bacterium Orientia tsutsugamushi Targets NLRC5 To Modulate the Major Histocompatibility Complex Class I Pathway

Abstract

Orientia tsutsugamushiis an obligate intracellular bacterium that infects mononuclear and endothelial cells to cause the emerging global health threat scrub typhus. The ability ofO. tsutsugamushito survive in monocytes facilitates bacterial dissemination to endothelial cells, which can subsequently lead to several potentially fatal sequelae. As a strict intracellular pathogen that lives in the cytoplasm of host cells,O. tsutsugamushihas evolved to counter adaptive immunity. How the pathogen does so and the outcome of this strategy in monocytes versus endothelial cells are poorly understood. This report demonstrates thatO. tsutsugamushireduces cellular levels of NOD-, LRR-, and CARD-containing 5 (NLRC5), a recently identified specific transactivator of major histocompatibility complex class I (MHC-I) component gene expression, to inhibit MHC-I biosynthesis. Importantly, the efficacy of this approach varies with the host cell type infected. In nonprofessional antigen-presenting HeLa and primary human aortic endothelial cells, theO. tsutsugamushi-mediated reduction of NLRC5 results in lowered MHC-I component transcription and, consequently, lower total and/or surface MHC-I levels throughout 72 h of infection. However, in infected THP-1 monocytes, which are professional antigen-presenting cells, the reductions in NLRC5 and MHC-I observed during the first 24 h reverse thereafter.O. tsutsugamushiis the first example of a microbe that targets NLRC5 to modulate the MHC-I pathway. The differential ability ofO. tsutsugamushito modulate this pathway in nonprofessional versus professional antigen-presenting cells could influence morbidity and mortality from scrub typhus.

The MHC Class-I Transactivator NLRC5: Implications to Cancer Immunology and Potential Applications to Cancer Immunotherapy

“…This study showed that the lncRNA XIST (X-inactivation-specific transcript), upregulated in breast cancer cells, promotes cell proliferation, migration and invasion by increasing NLRC5 expression through sponging off miR-125b-5p. An obligate intracellular bacterium Orientia tsutsugamushi , which causes scrub typhus by infecting mononuclear and endothelial cells, was shown to attenuate NLRC5 expression in HeLa cells at the post-transcriptional level [ 203 ]. The blockade of NLRC5 protein expression by O. tsutsugamushi required bacterial protein synthesis and possibly host cell factors as inhibition of NLRC5 protein expression was reversible in a monocytic cell line THP-1 but not in endothelial cells.…”

Selective fragmentation of the trans-Golgi apparatus by Rickettsia rickettsii

“…Some may more generally disrupt anterograde protein trafficking and thereby inhibit or slow MHC-1 trafficking to the cell surface [19]. An intracellular bacterium, Orientia tsutsugamushi, may also utilize specific and non-specific means to inhibit MHC-1 delivery to the cell surface [42]. Virulent R. rickettsii displays a dramatic and apparently global down-regulation of anterograde protein trafficking to the plasma membrane.…”

MHC class I transactivator NLRC5 in host immunity, cancer and beyond

“…Nlrc5 knockout mice demonstrate increased bacterial loads of Listeria monocytogenes upon infection 29,33 and reduced viral clearance of influenza A and rotavirus attributed to both reduced basal splenic CD8 + T cells as well as impaired CD8 + T‐cell effector function 34,35 . These observations suggest that targeting the ‘signal transducer and activator of transcription 1–NLRC5–MHC class I’ axis is an attractive strategy for intracellular bacteria to evade host immune responses 36,37 …”