A Novel Model of Asymptomatic Plasmodium Parasitemia That Recapitulates Elements of the Human Immune Response to Chronic Infection

Abstract

In humans, immunity to Plasmodium sp. generally takes the form of protection from symptomatic malaria (i.e., 'clinical immunity') rather than infection ('sterilizing immunity'). In contrast, mice infected with Plasmodium develop sterilizing immunity, hindering progress in understanding the mechanistic basis of clinical immunity. Here we present a novel model in which mice persistently infected with P. chabaudi exhibit limited clinical symptoms despite sustaining patent parasite burdens for many months. Characterization of immune responses in persistently infected mice revealed development of CD4+ T cell exhaustion, increased production of IL-10, and expansion of B cells with an atypical surface phenotype. Additionally, persistently infected mice displayed a dramatic increase in circulating nonclassical monocytes, a phenomenon that we also observed in humans with both chronic Plasmodium exposure and asymptomatic infection. Following pharmacological clearance of infection, previously persistently infected mice could not control a secondary challenge, indicating that persistent infection disrupts the sterilizing immunity that typically develops in mouse models of acute infection. This study establishes an animal model of asymptomatic, persistent Plasmodium infection that recapitulates several central aspects of the immune response in chronically exposed humans. As such, it provides a novel tool for dissection of immune responses that may prevent development of sterilizing immunity and limit pathology during infection.

Macrophage Colony Stimulating Factor Derived from CD4+ T Cells Contributes to Control of a Blood-Borne Infection

“…chabaudi infection. Among other subsets, we considered a role for CD4 + T helper cells, whose importance in controlling blood-stage Plasmodium has been suggested in humans [30–32] and demonstrated in mice [33–37]; infected mice depleted of CD4 + T cells exhibit defects in parasite control reminiscent of those observed after late macrophage depletion [35,28,37,38] ( Fig 1D ). Accordingly, we found that depletion of CD4 + T cells 4 d.p.i.…”

FCRL5+ Memory B Cells Exhibit Robust Recall Responses

“…We previously reported that Ifngr1 −/− mice chronically infected with P. chabaudi (patent parasitemia persisting >100 days) develop high frequencies of class-switched FCRL5 + B cells in the blood ( Fontana et al, 2016 ). To build on this observation, we performed global transcriptional profiling on class-switched, FCRL5 + or FCRL5 − B cells sorted from acutely infected Ifngr1 −/− mice 21 d.p.i., when FCRL5 + cells are abundant in circulation (gating in Figure S2 ).…”

“…Several lines of evidence support the contention that FCRL5 + murine MBCs are analogous to human atMBCs. Following a single Plasmodium infection, both populations expand in the blood and then contract as infection is cleared ( Figure 1C ; Scholzen et al, 2014 ; Sullivan et al, 2016 ), whereas chronic or repeated infection leads to a sustained increase in frequency ( Fontana et al, 2016 ; Weiss et al, 2009 ). When examined during acute infection, FCRL5 + B cells exhibit expression patterns comparable to human atMBCs for a substantial number of immune- related genes, perhaps most notably the master transcription factor T-bet.…”

“…Although P. chabaudi is considered a chronic model, with parasites persisting up to 3 months, it is possible that it does not adequately replicate the chronic conditions of repeated human exposure to Plasmodium , which may alter the functional capacity of atMBCs. Further studies in persistently infected mice ( Fontana et al, 2016 ) are planned to address this critical issue. Interestingly, atMBCs from HIV viremic patients produced more HIV-specific antibodies than cMBCs ( Moir et al, 2008 ), suggesting that these cells can retain secre- tory capacity despite chronic antigen exposure.…”

Monocyte dysregulation and systemic inflammation during pediatric falciparum malaria

“…The level of inflammation appears to be dependent on the density of blood-stage infection and, by inference, P. falciparum biomass, as children with asymptomatic infection detectable by blood smear had higher levels of inflammation compared with uninfected children as well as children who were P. falciparum PCR positive but blood smear negative. Others have shown an association of asymptomatic P. falciparum infection in children with increased proportions of circulating CD16 + monocytes (43), anemia, and increased markers of systemic inflammation (44). Impaired phagocytosis by dendritic cells has been associated with submicroscopic parasitemia in malaria-naive adult volunteers experimentally challenged with P. falciparum-IEs (45).…”