Abstract
Leptospirosis is a re-emerging tropical infectious disease caused by pathogenic Leptospira spp. The different host innate immune responses are partially related to the different severities of leptospirosis. In this study, we employed transcriptomics and cytokine arrays to comparatively calculate the responses of murine peritoneal macrophages (MPMs) and human peripheral blood monocytes (HBMs) to leptospiral infection. We uncovered a series of different expression profiles of these two immune cells. The percentages of regulated genes in several biological processes of MPMs, such as antigen processing and presentation, membrane potential regulation, and the innate immune response, etc., were much greater than those of HBMs (>2-fold). In MPMs and HBMs, the caspase-8 and Fas-associated protein with death domain (FADD)-like apoptosis regulator genes were significantly up-regulated, which supported previous results that the caspase-8 and caspase-3 pathways play an important role in macrophage apoptosis during leptospiral infection. In addition, the key component of the complement pathway, C3, was only up-regulated in MPMs. Furthermore, several cytokines, e.g. interleukin 10 (IL-10) and tumor necrosis factor alpha (TNF-alpha), were differentially expressed at both mRNA and protein levels in MPMs and HBMs. Some of the differential expressions were proved to be pathogenic Leptospira-specific regulations at mRNA level or protein level. Though it is still unclear why some animals are resistant and others are susceptible to leptospiral infection, this comparative study based on transcriptomics and cytokine arrays partially uncovered the differences of murine resistance and human susceptibility to leptospirosis. Taken together, these findings will facilitate further molecular studies on the innate immune response to leptospiral infection.
Highlights
Leptospirosis is an important tropical infectious disease around the world, in humid tropical and subtropical countries [1,2]
The virulence of L. interrogans was preserved by iteratively infecting specific pathogen-free Dunkin-Hartley ICO: DH (Poc) guinea pigs (10 to 12 days old; each weighing less than 150 g)
Unlike the heat-killed Leptospira used in prior infection models [16], a live and strong virulent L. interrogans strain was used to infect primary macrophages to establish the cell infection model in this study
Summary
Leptospirosis is an important tropical infectious disease around the world, in humid tropical and subtropical countries [1,2]. The causal agents include several pathogenic Leptospira spp., of which the highly virulent strains (e.g. Leptospira interrogans) chronically infect reservoir hosts (e.g. wild rodents) without causing severe symptoms; L. interrogans acutely infects humans and causes severe organ failure and mortality in some individuals. The urine released from a chronically infected reservoir host contains a high concentration of leptospiral cells, which can survive and replicate in moist soil and water for a long time before infecting the subject. The pathogen can infect humans through mucous membranes or abrasions in the skin, penetrate into the blood stream, and rapidly diffuse into the liver, lung, kidney, and other organs [1]. The clinical symptoms are complex, including hemorrhage, diarrhea, jaundice, severe renal impairment, aseptic meningitis, etc. Multiple components of the pathogen, such as lipopolysaccharide (LPS) [3], peptidoglycans [4], glycolipoproteins [5], lipoproteins [6], and transmembrane or outer membrane proteins (OMPs) [6], are involved in induction of the host immune response and cytokine secretion
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