MHV68 and Plasmodium co-infection Open Access

Matar, Caline (2015)

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Plasmodium infection causes nearly 1 million deaths annually, mostly comprising children younger than 5 years of age. Children living in areas endemic for P. falciparum transmission are thought to acquire immunity to non-cerebral severe forms of disease within 1-2 infections, however, 10-20% of these children progress to severe disease. P. falciparum infection is highly associated with Epstein-Barr Virus (EBV) co-infection in Sub-Saharan Africa. Children repeatedly infected with P. falciparum have an increased risk of developing endemic Burkitt's lymphoma (eBL). EBV specific CD8+ T cell responses were shown to be attenuated in eBL patients and are thought to be a consequence of repeated and high exposure rates to P. falciparum infection. One aspect of such co-infections that has largely been neglected is the role of a primary asymptomatic EBV infection in modulating immunity to malaria. Asymptomatic EBV infection has been shown to suppress the humoral immune response transiently, and this may render a host susceptible to secondary infections. Co-infection with the Murine gammaherpesvirus 68 (MHV68) transforms the non-lethal P. yoelii XNL, but not P. chabaudi AS, infection into a lethal one. We demonstrate that MHV68 induces a transient suppression of the humoral immune response, which was marked by suppressed levels of germinal center B cells, plasma cells and T follicular helper cells in the spleen. This effect was dependent on the late acute phase of viral replication, but not long term latency. More importantly, we identify the M2 gene product as a facilitator of the virus induced humoral suppression. Co-infection with the M2 null virus and P. yoelii resulted in 94% survival and rescued the parasite specific IgG response by 28 fold. We next evaluated the impact of such co-infection on the development of long term memory B cell responses during a P. chabaudi co-infection model by evaluating BCR clonal diversity. Taken together, my thesis work has identified a potential role for EBV, which ubiquitously infects the population, in having substantial effects on the host immune response, thereby predisposing the host to secondary opportunistic infections. This novel finding largely supports efforts directed towards the development of EBV specific anti-viral drugs and vaccines.

Table of Contents

Chapter I - Introduction

I. Co-infection with EBV and P. falciparum. 1

II. Can gammaherpesviruses alter pathogenesis to malaria?. 3

a. Rodent models of malaria infection. 3

b. The MHV68 rodent model of gammaherpesvirus infection. 4

c. Co-infection with MHV68 and malaria in rodent models. 7

III. Gammaherpesvirus induced suppression of the innate immune response to malaria. 8

IV. Modulation of CD8+ T cell responses during EBV and P. falciparum co-infection. 11

V. Impairment of anti-malarial humoral response by gammaherpesvirus co-infection. 13

VI. Conclusions. 15

Figures. 16

Figure Legends. 19

Chapter II - Gammaherpesvirus co-infection promotes malaria lethality by impairing the generation of anti-parasitichumoral immunity. 20

Introduction. 21

Materials and Methods. 24

Results. 28

Discussion. 38

Figures. 45

Figure legends. 58

Chapter III Murine gammaherpesvirus 68 reactivation from B cells requires IRF4, but not XBP-1. 63

Introduction. 64

Materials and Methods. 67

Results. 71

Discussion. 77

Figures. 80

Figure Legends. 88

Chapter IV - Summary, future directions and conclusions. 91

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