Few scientists view the immune system as a binary between human and nonhuman infection. In many cases—dozens known for certain to science, and likely thousands or millions given the variety of life forms in animal bodies—bacteria and viruses have evolved along with more complicated organisms, becoming inextricably linked to health. It may not be accurate to describe these ancient intruders as separable from a “healthy” body—although, strictly speaking, they are undeniably infections.
The human immune system and its bacterial allies aren’t the only line of defense against hostile diseases, though. As scientists reevaluate what constitutes immunity on an individual level, the health of vectors, the means by which hostile viruses and bacteria are transmitted into human bodies, has taken on a new significance.
“A vector is an organism that serves as a necessary intermediary for human disease, or other animal diseases,” says Leonard Munstermann, PhD, a senior research scientist in epidemiology (microbial diseases) at the Yale School of Public Health. Munstermann focuses on population genetics and taxonomic relationships among the 400 species of South American phlebotomine sand flies, some of which are responsible for spreading leishmaniasis.
Past efforts to control vectors have included wildly destructive assaults on the environment. Alongside developing medical technology, ecological awareness has led to other ways to affect vectors. Most recently these include attempts to strengthen their immune systems against infection. Researchers hope to preserve animals and microbes that may be crucial to the food chain in some manner that isn’t understood today while removing the threat that they pose to human populations.
“Especially for the parasitic protozoans, which have few convenient antibiotic cures, targeting the vectors themselves is a promising route for researchers,” says Munstermann. “Sand flies, mosquitos like the dreaded Asian Tiger Aedes albopictus, ticks, tsetse flies, and other arthropods harbor within them a host of debilitating diseases that are anathema to human health.”
A longtime source of illness and debilitation for humans, ticks are a vector that has rebounded as New England farmland has receded and forests have regrown. Sukanya Narasimhan, PhD, FW ’93, a senior research scientist in the Section of Infectious Diseases, studies the microbiome of the deer tick in collaboration with Erol Fikrig, MD, FW ’92, the Waldemar von Zedtwitz Professor of Medicine (Infectious Diseases), professor of epidemiology (microbial diseases), of microbial pathogenesis, and chief of the Section of Infectious Diseases. Together the two researchers hope to identify ways to reduce the tick’s ability to host pathogens that are dangerous to humans and human-adjacent animals.
Narasimhan says that as evidence mounted about the mammalian microbiomes and their impact on human health, “We wondered if ticks might harbor microbiota, and if their indigenous bacteria affect the tick, how it acquires pathogens, and how it passes them on to us.”
She adds, “Tick prevalence doesn’t necessarily mean infection prevalence, so there could be parts of the United States where you have a lot of ticks, but infection is not very high. This is also the case with mosquitoes in India. Many factors, intrinsic and extrinsic, influence infection prevalence—this is complex. We wanted to examine whether the tick gut microbiome might represent one factor, and if shifts in the tick’s microbiome might contribute to the tick’s ability to host and transmit the pathogens.”
Research conducted by several groups into the lives of African mosquitoes suggests that mosquitoes’ gut microbiota influence the survival of their malaria-causing parasites. Articles published in the last decade uncovered correlations between bacteria present in arthropods like Aedes aegypti and resistance to such deadly pathogens as (in the case of Aedes aegypti) the dengue virus.
Narasimhan and Fikrig’s efforts indicate that the microbiome of ticks does play some role in ticks’ “health” in the context of how they acquire pathogens and how they molt, but the researchers are still working to establish the precise nature of that role, as well as which microbiota or subset of microbiota observed in ticks might play a significant role.
Ultimately, Fikrig and Narasimhan hope that if we understand how the tick microbiome influences tick-borne pathogens, it may be possible to leverage that knowledge to reduce the prevalence (if not the virulence) of tick-borne diseases.
Serap Aksoy, PhD, FW ’88, professor of epidemiology (microbial diseases) in the Yale School of Public Health, has battled the protozoan parasites that cause African trypanosomiasis (more commonly known as “African sleeping sickness,” which is fatal if untreated) for decades. Her research into the insect vector primarily responsible for spreading the disease—the tsetse fly—has resulted in numerous breakthroughs: most recently, a mechanism that reduces the fly’s ability to transmit disease-causing trypanosomes.
“One of the more interesting characteristics of the tsetse fly is its mode of reproduction,” says Brian Weiss, PhD, FW ’08, research scientist and lecturer in epidemiology (microbial diseases) in the School of Public Health. Weiss, who works in Aksoy’s lab, knows a great deal about the topic. “Tsetse flies reproduce through a process called adenotrophic viviparity, which means gland-fed live birth. In this situation, embryonic and larval stages (one per reproductive cycle) occur within the mom’s uterus, and the larva receives nourishment in the form of milk secreted by a modified accessory gland.” In contrast, almost all other female insects will lay a clutch of fertilized eggs into their environment and hope that a couple of them reach sexual maturity.”
Aksoy and her research team discovered that tsetse milk also contains symbiotic bacteria that mediate numerous aspects of the fly’s physiology. One of these microbes, the Wigglesworthia species (named after the famous British entomologist who first described it) shares an obligate association with its tsetse host. Without Wigglesworthia, which produces essential nutrients missing from tsetses’ vertebrate blood specific diet, adult flies present a severely compromised immune system and are reproductively sterile. This research provides useful insights for developing control strategies aimed at reducing tsetse population size and/or inhibiting the fly’s ability to transmit trypanosomes.
Tsetse flies house other symbiotic bacteria that may also reduce disease transmission. “Most tsetse flies harbor a commensal bacterium from the genus Sodalis (which means ‘companion’ in Latin) that, similar to Wigglesworthia, is passed from mother to larva via milk. This bacterium can live outside of its host and be genetically modified. If we can customize Sodalis to produce a trypanocidal protein, and then return these bacteria to the fly, they may become more resistant to infection,” says Aksoy. These characteristics make Sodalis an attractive target for research.
“We’ve designated insects that carry genetically modified symbionts as ‘paratransgenic,’ ” says Aksoy. “And one of these days, they might help wipe out some of humanity’s most prolific killers.”