Liver Accumulation of Plasmodium chabaudi-Infected Red Blood Cells and Modulation of Regulatory T Cell and Dendritic Cell Responses

Abstract

It is postulated that accumulation of malaria-infected Red Blood Cells (iRBCs) in the liver could be a parasitic escape mechanism against full destruction by the host immune system. Therefore, we evaluated the in vivo mechanism of this accumulation and its potential immunological consequences. A massive liver accumulation of P. c. chabaudi AS-iRBCs (Pc-iRBCs) was observed by intravital microscopy along with an over expression of ICAM-1 on day 7 of the infection, as measured by qRT-PCR. Phenotypic changes were also observed in regulatory T cells (Tregs) and dendritic cells (DCs) that were isolated from infected livers, which indicate a functional role for Tregs in the regulation of the liver inflammatory immune response. In fact, the suppressive function of liver-Tregs was in vitro tested, which demonstrated the capacity of these cells to suppress naive T cell activation to the same extent as that observed for spleen-Tregs. On the other hand, it is already known that CD4+ T cells isolated from spleens of protozoan parasite-infected mice are refractory to proliferate in vivo. In our experiments, we observed a similar lack of in vitro proliferative capacity in liver CD4+ T cells that were isolated on day 7 of infection. It is also known that nitric oxide and IL-10 are partially involved in acute phase immunosuppression; we found high expression levels of IL-10 and iNOS mRNA in day 7-infected livers, which indicates a possible role for these molecules in the observed immune suppression. Taken together, these results indicate that malaria parasite accumulation within the liver could be an escape mechanism to avoid sterile immunity sponsored by a tolerogenic environment.

Blood-Stage Plasmodium Berghei ANKA Infection Promotes Hepatic Fibrosis by Enhancing Hedgehog Signaling in Mice

“…Infected erythrocytes are known to cytoadhere to small capillaries and post-capillary venules in host tissue, and this process is called sequestration [38,39]. Liver is one of organs in which iRBCs preferentially accumulate to avoid immune system surveillance inside the spleen, and iRBC sequestration within the liver endothelium is now emerging as another factor that promotes liver damage [40][41][42]. Several studies suggest that iRBC sequestration contributes to the intrahepatic obstruction of blood flow, which leads to hepatocellular hypoxia and excessive intravascular hemolysis, causing increased oxidative stress and leukocyte infiltration [40,[43][44][45].…”

“…Liver is one of organs in which iRBCs preferentially accumulate to avoid immune system surveillance inside the spleen, and iRBC sequestration within the liver endothelium is now emerging as another factor that promotes liver damage [40][41][42]. Several studies suggest that iRBC sequestration contributes to the intrahepatic obstruction of blood flow, which leads to hepatocellular hypoxia and excessive intravascular hemolysis, causing increased oxidative stress and leukocyte infiltration [40,[43][44][45]. Infiltrated leukocytes also produce inflammatory mediators, thereby enhancing hepatic inflammation [43,46].…”

Coinfection with Blood-Stage Plasmodium Promotes Systemic Type I Interferon Production during Pneumovirus Infection but Impairs Inflammation and Viral Control in the Lung

“…For example, it has been shown that PcAS infection can enhance Foxp3 ϩ regulatory T-cell (Treg) responses in peripheral tissues, such as the liver (24). Therefore, it is at least theoretically possible that PcAS coinfection also boosts Treg responses in the lung.…”

Regulator Versus Effector Paradigm: Interleukin-10 as Indicator of the Switching Response

“…Early-stage infection IL-10 synthesis can also involve the neutrophils, because inhibition of IL-10 signaling abrogated the increase in Leshmania parasite loads in BALB/c mice during the first week [89]. Apart from acute phase infections, the IL-10 involvement during the first week is observed even in intracellular pathogens, tumors, and transplants, which demonstrate implication of PMCs, NK, and CD4+ T cells in the IL-10 synthesis [130,156,158,165,166]. Increased IL-10 production by CD4CD25FoxP3+ T cells along few weeks was observed in a time-dependent manner during melanoma tumor growth in mice, while the initial association of IL-10 production with migration of macrophages, DCs, and neutrophils following peritoneal scaffold implantation was replaced by association with T lymphocytes that became prevalent by day 14 [124,142].…”