Vector-borne bacterial diseases: a neglected field of infectious diseases research

Arthropod-borne bacterial diseases are among the oldest vector-borne illnesses described. In 1898, just a decade after the first description of Bancroftian filariasis (1), the first vector-borne disease ever described, Sir Ronald Ross famously pioneered the field by demonstrating the role of mosquitoes as vectors of malaria parasites while working in India (2). In the very same year in neighboring Pakistan, Paul Louis Simond demonstrated that Xenopsylla fleas could transmit Yersinia pestis, the etiologic agent of plague (3). Since then, dozens of arthropod-borne bacterial agents have been reported. Highly virulent vector-borne bacterial diseases, such as Rocky Mountain spotted fever and epidemic typhus caused by Rickettsia rickettsii (4) and R. prowazekii (5), respectively, were described at the beginning of the 20th century, so was Lyme disease (6). In tropical areas, vector-borne bacterial diseases are often confused with other more common febrile illnesses, such as malaria or mosquito-borne viral diseases. Indeed, most arthropod-borne bacterial pathogens cause acute febrile illnesses associated with non-specific symptoms such as malaise, myalgia, fever, headaches, nausea, etc (7-10). The dearth of specific symptoms makes the diagnosis particularly challenging, especially in areas and populations with a high risk of infectious diseases. Yet, arthropod-borne bacterial pathogens can cause mild to very severe human diseases. Several arthropod-borne bacterial pathogens such as Rickettsia, Ehrlichia, Anaplasma, and Orientia spp. are obligate intracellular pathogens targeting the vertebrate host endothelial cells, especially those in the lungs and brain (11), causing a perivascular inflammatory response in these organs as well as in the heart muscle, testes, and kidneys (12). Severe disease associated with these pathogens can be associated with pulmonary edema and central nervous system manifestations such as coma, potentially leading to death if no targeted antibiotic treatment is administered (11). Most of the symptoms associated with Borrelia spp. infections, including the more neglected relapsing fever Borrelia species, are secondary to the host's immune response against the spirochete and the resulting inflammation (13). As for Coxiella burnetii, this obligate intracellular pathogen can infect both epithelial and endothelial cells after infecting its primary niche, phagocytic cells. Chronic Q fever may then be associated with endocarditis and hepatitis (14). Finally, at least 13 Bartonella species—or subspecies—have been recognized as human pathogens. They are opportunistic pathogens infecting erythrocytes and endothelial cells throughout the body, causing a variety of potentially severe clinical manifestations such as endocarditis, retinitis, encephalitis, bacillary angiomatosis/peliosis, etc (15). Most of these agents are emergent or reemergent zoonotic pathogens with species distributed worldwide, which are associated with various animal reservoirs, including wildlife and/or domestic animals—pets and farm animals (13-16). Humans are in contact with other animals more than ever: many pets have been adopted (and many relinquished) since the beginning of the COVID-19 pandemic —partly due to new work-from-home habits and isolation (17), many touristic activities focused on wildlife are highly popular (visiting bat caves, safaris, non-human primate excursions) and sometimes offer close contact with the animals, and finally, the constant urban development of our environment is bringing us closer and closer to wildlife habitats. Global warming is also expanding the distribution area and seasonal patterns of arthropod vectors and, therefore, of the pathogens they may carry and transmit (18, 19). This proximity to potential reservoirs of zoonotic pathogens has highlighted and heightened the need to monitor these microorganisms thoroughly. The development of molecular biology approaches has provided more opportunities to perform surveillance of microorganisms, broader panels of tests for febrile patients, and new methods to classify and study microorganisms, including arthropod-borne bacterial pathogens. This expansion of medical entomology research and diagnosis allowed the identification of many bacterial agents, which were later determined as arthropod-borne bacterial pathogens (16). However, despite the progress made in describing arthropod-borne bacterial pathogens, most of them remain highly neglected. Dengue and malaria are jointly responsible for hundreds of thousands of cases yearly in tropical areas, including thousands of deaths (WHO). The explosive Zika outbreak reinforced the focus on mosquito-borne viral diseases. Lyme disease excluded, vector-borne bacterial disease research is significantly neglected in comparison (20). This can be due to several factors. First, the joint burden of malaria and dengue is colossal in comparison to that of illnesses caused by arthropod-borne bacterial diseases. Additionally, many arthropod-borne bacterial pathogens circulate in countries with limited scientific research resources, hindering surveillance efforts. Some of these pathogens, such as R. prowazekii and B. recurrentis, are carried and transmitted by body lice, primarily found in association with vulnerable populations living in crowded environments with limited/inadequate sanitation, such as unhoused people, refugees, civilians in a war zone, etc (13). Scientific research involving human participants, especially vulnerable populations, is rigorously controlled by multiple stringent regulations. It is a highly challenging process, from obtaining ethical approvals to setting up a study in areas with little to no infrastructure, limiting the number of studies conducted in these environments. Finally, the impact of these studies is occasionally perceived as being restricted to the study population, which limits the number of funding opportunities. Nevertheless, vector-borne bacterial diseases are still a global issue that deserve to be addressed. For example, Rocky Mountain spotted fever is a life-threatening tick-borne bacterial disease prevalent in the Americas. Indeed, Rickettsia rickettsii is currently a major etiology of acute undifferentiated fever in Latin America, where fatality rates are above 40%, compared to less than 10% in the United States, with important outbreaks in Native American tribal lands in Arizona (21). In many regions, precise data on circulating arthropod-borne bacterial pathogens needs to be generated and made available. The Zika outbreak perfectly illustrated that the surveillance of vector-borne pathogens must be global. If surveillance efforts are impeded by the availability of resources or specific expertise, those efforts should be supported within the context of an equitable partnership (22). Aside from surveillance, several facets of vector-borne bacterial disease research must be investigated more extensively. First, a significant amount of data is being generated on microorganisms detected in potential vectors using molecular biology. There is a need to explore the vector competence of these arthropods for these bacterial agents through well-designed transmission models. The description of the pathogenesis of many vector-borne bacterial pathogens is still incomplete, even though virulence studies could lead to identifying drug or vaccine targets. Finally, vector-borne obligate intracellular bacteria are a step behind when it comes to genetic manipulation. Few studies have focused on these bacteria's whole genome sequencing and genetic manipulation, limiting molecular biology approaches to study pathogenesis, virulence, transmission, etc., as comfortably as with other more malleable bacteria. In conclusion, although the burden of bacterial arthropod-borne bacterial diseases remains lower than the joint burden of parasitic and viral arthropod-borne diseases, there is an undeniable need to study these neglected pathogens. Significant gaps in their ecology, transmission or pathogenesis still need to be filled.