Gammaherpesvirus Co-infection with Malaria Suppresses Anti-parasitic Humoral Immunity

Abstract

Immunity to non-cerebral severe malaria is estimated to occur within 1-2 infections in areas of endemic transmission for Plasmodium falciparum. Yet, nearly 20% of infected children die annually as a result of severe malaria. Multiple risk factors are postulated to exacerbate malarial disease, one being co-infections with other pathogens. Children living in Sub-Saharan Africa are seropositive for Epstein Barr Virus (EBV) by the age of 6 months. This timing overlaps with the waning of protective maternal antibodies and susceptibility to primary Plasmodium infection. However, the impact of acute EBV infection on the generation of anti-malarial immunity is unknown. Using well established mouse models of infection, we show here that acute, but not latent murine gammaherpesvirus 68 (MHV68) infection suppresses the anti-malarial humoral response to a secondary malaria infection. Importantly, this resulted in the transformation of a non-lethal P. yoelii XNL infection into a lethal one; an outcome that is correlated with a defect in the maintenance of germinal center B cells and T follicular helper (Tfh) cells in the spleen. Furthermore, we have identified the MHV68 M2 protein as an important virus encoded protein that can: (i) suppress anti-MHV68 humoral responses during acute MHV68 infection; and (ii) plays a critical role in the observed suppression of anti-malarial humoral responses in the setting of co-infection. Notably, co-infection with an M2-null mutant MHV68 eliminates lethality of P. yoelii XNL. Collectively, our data demonstrates that an acute gammaherpesvirus infection can negatively impact the development of an anti-malarial immune response. This suggests that acute infection with EBV should be investigated as a risk factor for non-cerebral severe malaria in young children living in areas endemic for Plasmodium transmission.

IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection

“…CD4 + T-cells are critical for control and resolution of blood-stage Plasmodium infection [4,11,45], a phenomenon we first confirmed in Py 17XNL-infected WT mice depleted of CD4 + cells (Fig 1A & 1B). Despite this, to our knowledge there remained no direct evidence that CD4 + T cells promoted B-cell responses during experimental malaria.…”

“…Mouse models of resolving, non-lethal blood-stage Plasmodium infection are useful for studying humoral immunity to malaria, since mice fail to control parasitemias and display increased disease severity in the absence of parasite-specific antibodies [4,11,12,13,14]. However, our understanding of how humoral immune responses develop in these models is currently modest.…”

Impaired B cell function during viral infections due to PTEN-mediated inhibition of the PI3K pathway

“…Depending on the pathogen and the timing of immunization or secondary infection, immune responses can be enhanced or suppressed. Whereas enhancement of immune responses can be advantageous to the host (Barton et al, 2007;Furman et al, 2015), suppression can have dire consequences (Elsner et al, 2015;Matar et al, 2015).…”

Coinfections: Another Variable in the Herpesvirus Latency-Reactivation Dynamic

“…However, gammaherpesvirus infection can also exacerbate disease. For example, latent infection with MHV68 increases the severity of experimental autoimmune encephalomyelitis (EAE), as well as the mortality rate of mice infected with malaria parasites (1,8,9). The mechanisms underlying these differences in outcomes are not well understood; however, different inflammatory responses are a likely explanation.…”