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Vector-Pathogen-Host Interactions

Research Summary

Erol Fikrig is studying the relationship between pathogens, the vectors that carry them, and the hosts they infect, and looking for ways to interrupt those relationships to prevent or treat disease.

Arthropod-borne infectious diseases remain an international public health concern. To prevent or treat these illnesses, I am developing new strategies based on an understanding of the intimate relationship between the vector, pathogen, and mammalian host. My laboratory focuses on three arthropod-transmitted diseases to explore these interactions. Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most common tick-borne illness in the United States. Anaplasma phagocytophilum, an obligate intracellular bacterium that persists within neutrophils, causes human granulocytic anaplasmosis and is primarily transmitted by Ixodes ticks. Finally, West Nile virus, a mosquito-borne flavivirus that recently emerged in North America, causes severe encephalitis.

Lyme disease was used as a model to show that immunization with B. burgdorferi outer surface protein (Osp) A is protective against infection. This led to an FDA-approved human Lyme disease vaccine. Surprisingly, antibodies elicited by the vaccine enter the tick when the arthropod feeds, and then destroy OspA-producing B. burgdorferi in the vector. As OspA is normally down-regulated by spirochetes during transmission from ticks to humans, this demonstrates an unusual mechanism of vaccine action—the targeting of an antigen expressed by a microbe within the vector to protect humans from infection.

Figure 1: Ixodes scapularis tick...

My laboratory is interested in how pathogens may use arthropod products to facilitate infection of the mammalian host. As B. burgdorferi migrate from ticks to humans, the spirochetes influence the expression of tick salivary gland genes. B. burgdorferi then bind to some of the induced salivary proteins, such as Salp15, and use the tick proteins to evade mammalian immune responses. These discoveries led to the paradigm that microbes may use specific arthropod molecules to enable successful infection of the host—a triangular interaction at the ephemeral pathogen-vector-host interface that occurs while an arthropod is feeding on a vertebrate.

I am also determining whether, to be successfully acquired by the vector, pathogens within mammals use arthropod proteins that are secreted into the host. For example, ticks engorging on vertebrates induce recruitment of inflammatory cells to the bite site. For efficient migration to the vector, pathogens must traffic through this complex environment while avoiding the deleterious effects of immune cells. The tick salivary protein Salp25D plays a critical role in the mammalian host for acquisition of Borrelia burgdorferi by the arthropod. Salp25D detoxifies reactive oxygen species at the vector-pathogen-host interface, providing a survival advantage to B. burgdorferi at the tick-feeding site in mice. Silencing salp25D impairs spirochete acquisition by ticks engorging on B. burgdorferi–infected mice. These data demonstrate that pathogens can exploit arthropod molecules to defuse mammalian responses in order to enter the vector.

I am studying whether these paradigms—initially established with B. burgdorferi—are applicable to other arthropod-borne infectious agents, including A. phagocytophilum and West Nile virus. My lab is also developing techniques to identify the entire panel of vector genes that are induced or repressed by pathogens, and assays to delineate the complete profile of arthropod proteins that microbes adhere to, or otherwise interact with. We are also assessing whether colonization of arthropods by specific infectious agents is a mutualistic, rather than parasitic, relationship. Understanding these interactions may lead to new ways to interrupt the life cycle of arthropod-borne pathogens and new vaccine strategies against these diseases.

This work is also supported by the National Institutes of Health.

As of November 1, 2013

Scientist Profile

Investigator
Yale University
Immunology, Microbiology