Parasite-Derived Vesicles in Babesia virulence and Vaccine Development

Research Summary:
The May 2018 edition of CDC Morbidity and Mortality Weekly Report (MMWR) highlighted the alarming increase
in the number of reported vector-borne disease cases in the United States. Between 2004 and 2016, 491,000
(76%) vector-borne diseases were caused by tick-transmitted agents. One such disease is human babesiosis,
a potentially fatal and rapidly emerging tick-borne illness reported worldwide and endemic in the United States.
Nine species of Babesia distributed into 2 major groups (small and large Babesia) have been linked to infection
in humans. Small Babesia species encompass B. microti, which is responsible for most human cases worldwide
and B. duncani, which causes fulminant infection that leads to severe and often fatal outcome. Despite the
importance of babesiosis in public health, little is known about the biology, pathogenesis, and mechanism of
virulence of Babesia parasites. We found that, unlike other Apicomplexa, B. microti and B. duncani employ a
novel mode of communication with the host involving two mechanisms of protein export, one vesicular-mediated
and another non-vesicular-dependent. The molecular mechanisms underlying vesicular-mediated secretion in
Babesia and the role Babesia-derived vesicles (BDVs) play in parasite-host interactions remain to be elucidated.
We found that BDVs trigger strong immune modulation of host macrophages. Interestingly, our immunization
studies revealed that these vesicles also confer complete protection from subsequent Babesia challenge. The
overarching goal of this application is to unravel the molecular mechanisms by which Babesia spp communicate
with their host and leverage this knowledge to engineer an effective and safe vaccine for human babesiosis. This
goal will be achieved through three specific aims. In Aim 1, we will pursue further cell biological analyses to
elucidate the basic properties of the BDVs that confer immune protection. We will employ sub-fractionation
analyses to isolate vesicle populations based on size and origin, characterize their ability to confer immune
protection, and determine their structural constituents. In Aim 2, we will examine how BDVs elicit cellular and
humoral immune responses to gain insights into the mechanism of BDV-mediated immune protection. In Aim 3,
we will translate the knowledge about the structure, composition and function of BDVs to develop an effective
vaccine for human babesiosis. These studies are novel and are designed to help us better understand how
Babesia parasites that infect humans interact with the host, and to guide the development of new diagnostic
assays and therapies.

Grant Number: 1R56AI177660-01A1
NIH Institute/Center: NIH
Principal Investigator: CHOUKRI BEN MAMOUN