Early parasite-host interactions in controlled human malaria infection
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Date
06/02/2019Author
Milne, Kathryn Helen
Metadata
Abstract
Severe malaria infections cause over 400,000 deaths annually, mostly among African
children under 5 years of age. In order to reduce the burden of this disease, focus must
be placed on understanding what drives pathogenesis in those at greatest risk. It is
increasingly appreciated that early immune responses such as inflammation and
phagocytosis, although important for host defense, can also contribute to pathogenesis
when unrestrained. However, most studies of human malaria have been conducted at
the terminal stages of infection, making it difficult to identify the early immune events
that may be dictating clinical outcome. The expression of Plasmodium falciparum
erythrocyte membrane 1 (PfEMP1), along with other variant surface antigens (VSAs),
is also thought to influence disease severity, by mediating parasite-host interactions
that lead to obstruction of blood flow and organ dysfunction in the non-immune host.
Yet, whether these parasite proteins actually drive pathology has been difficult to
assess. It is likely that a contribution of both parasite genetics and host immune
responses is involved in the progression to severe disease, but how the two might
interact to drive this outcome has not yet been explored. Using controlled human
malaria infection (CHMI), this study aimed to: (1) characterise the early immune
response to P. falciparum during primary infection and investigate inter-individual
variability within the cohort, (2) assess patterns of parasite VSA expression during
infection in the malaria-naïve host and (3) determine the influence of parasite VSA
expression on the developing immune response, and vice versa.
Microarray analysis of the host (whole blood) response to P. falciparum revealed a
dichotomous pattern of gene expression, with volunteers demonstrating either up-regulation
or down-regulation of genes associated with the innate inflammatory
response, cell signaling and metabolism. This inter-individual variability correlated with
chemokine levels in the plasma and clinical adverse events, but not with parasite
growth in the circulation. RNA-sequencing of parasites, isolated from the blood of these
individuals, demonstrated broad-level expression of PfEMP1-encoding var genes.
However, expression was dominated by variants out-with those that have been
associated with severe disease, and was remarkably similar across samples from all
volunteers despite the observed diversity in host responses. Although we cannot
speculate as to the severity of outcome in the volunteers, these findings challenge
some key concepts in the field, for instance: (1) expression of group-A (disease
associated) PfEMP1 is not driving, nor is required for early disease outcome in malaria-naïve
individuals and (2) the host immune response is not directed by parasite gene
expression, and vice versa; the type of host immune response elicited has little
influence of parasite VSA expression early in infection. Focus should now be placed on
understanding the diversity of host immune responses produced during primary
P. falciparum infection, the clinical outcome(s) associated with these responses and
the host genetic/environmental factors that may serve to protect against severe malaria
disease.