Mysterious Wolbachia Bacterium Helps Fight the Dengue Virus

If you’re traveling to the Caribbean, Indonesia, Australia, or any tropical climate really (where else would you holiday), falling ill to the dengue virus may be in the back of your mind. And you would be smart to pack the mosquito repellant; dengue fever is a serious and potentially fatal disease without any specific treatment nor preventative medicine. More significantly, dengue burdens millions of people that inhabit the endemic habitat of Aedes aegypti, the carrier mosquito; endemicity that is rapidly spreading towards European and North American populations thanks to climate change. Over the past decade, reported dengue virus (DENV) cases to WHO has increased eight-fold to 5.2 million in 2019 [4]. Asia disproportionately represents 70% of the dengue burden, thought to be an effect of rapid urbanisation and global warming [1]. Thus, social and environmental issues should be taken into consideration when responding to the dengue outbreak. The lack of viable vaccines and specific treatment spotlights Wolbachia bacterium as a cheap and effective solution through a somewhat known, yet mysterious, symbiosis.

Figure 1: Mosquito image by Yogesh Pedamkar from Unsplash.

Dengue is a positive-strand RNA arboviral disease of the four serotypes DENV 1-4, belonging to the Flavivirus family [2]. Aedes aegypti mosquitoes are its primary vector, facilitating the carrying and spread of DENV amongst populations [3]. Humans also reservoir DENV, infecting mosquitoes who feed on them [4]. The route down DENV infection involves E proteins embedded within the viral lipid membrane, of which bind to cellular receptors to initiate endocytosis (entry into the cell for amplification and replication) [2]. Another pathway, the Antibody-Dependent Enhancement (ADE) pathway, is associated with greater disease severity or potentially fatal dengue shock syndrome. The ADE pathway exploits processes of the immune system. Fc immune cell receptors bind antibodies (bound to pathogen DENV) for endocytosis but also act to block key antiviral molecules such as cytokines, which are regulators of the immune response [5]. DENV acts to decrease transcription and translation of pro-inflammatory cytokines and increase transcription and translation of anti-inflammatory cytokines. Such imbalanced inflammatory responses cause inner blood vessel lining pathology and vascular leakage, leading to hypovolemic shock [2]. Dengue prevalence is attributed to Aedes aegypti’s life-long infectiousness and high transmission, but the spread of Dengue is compounded by social and environmental contributors discussed in coming chapters [2].

Wolbachia

To control the dengue burden, research in vaccines, antivirals, and vector-control has been discernible over the past decade [3]. However, lack of effective vaccines has left vector control the pertinent method for reducing viral spread [6]. Endosymbiont Wolbachia’s protection against significant infection of RNA viruses, and thus reduction of dengue infectivity in Aedes aegypti, has been known for years despite the lack of consensus on the underlying mechanisms. Wolbachia are maternally inherited bacteria known to infect >65% of insect species, yet do not naturally infect Aedes aegypti [7]. Fortunately artificial infection is feasible, thus, opening the door to potentially effective and naturally dispersive vector control.

Pan et al. [7] proposed the establishment of symbiosis between Wolbachia and its host to increase pathogen resistance. Wolbachia exploits host innate immunity by activating toll and immune deficiency (IMD) biochemical pathways. This is via activating pattern recognition receptors (proteins capable of recognising pathogenic molecules); both of which induce the expression of antimicrobial peptides, which in turn induce overexpression of antioxidants. Pan et al. acknowledge that it is unknown how these pathways reduce DENV infection and facilitate symbiosis, although it is clear upregulation of such pathways increases Wolbachia presence. For example, antioxidant enzymes induced by Toll pathways are suspected to enhance Wolbachia fitness [7]. This is supported in another study, where increasing fly survivability in hyperoxic conditions was shown to have high antimicrobial peptide and antioxidant presence [8]. Antimicrobial peptides potentially maintain the Wolbachia niche in preventing the growth of microbial flora within mosquitos [7]. As described above, Wolbachia’s exploitation of a host’s immune response allows it to beat its microbial competitors. Evidently, boosting mosquito immunity with Wolbachia could both amplify Wolbachia titer (populations) and resistance to DENV.

A secondary speculated mechanism suggests Wolbachia may out-compete DENV for important host cell components including cholesterol, by which Wolbachia nor Flavivirus’ have the biosynthetic capability to synthesise autonomously. Interestingly, DENV requires cholesterol in order to replicate and cause pathogenesis [6]. The significance of competition between Wolbachia and DENV is yet to be determined, however, it sounds like it could be a key area of focus in future studies.

Figure 2: Poor infrastructure, drainage and sanitation are depicted as a consequence of rapid urbanisation in Vietnam. Vietnam, like Bangladesh, manages the dengue burden seasonally and with increasing severity. Image by Tony Lam Hoang from Unsplash.

Thinking beyond Wolbachia

The importance of DENV control is reinforced when considering the implications of both urbanisation and global warming on the dengue burden. Aedes aegypti survival, reproduction and transmission are promoted by increase in temperature, annual precipitation and humidity [10]. Bangladesh exemplifies how Aedes aegypti exploit such climatic shifts where the 2015-2017 pre-monsoon season saw seven times more dengue cases than the 2000-2017 season [11]. Rapid urbanisation was also linked to increasing dengue cases in Bangladesh. Poor health care, infrastructure, sanitation, waste disposal, and drainage facilitates increased transmission and mortality in such metropolitan agglomerates [12]. Both global warming and urbanisation extend Aedes aegypti habitat beyond endemicity where human interaction with zoonotic (animalborne) disease increases with deforestation and extension into wild habitat whilst tropical boundaries continually stretch toward the poles [13]. In 2015, approximately 53% of the global population was modeled to inhabit dengue risk areas, and was projected to increase to 60% in 2080 [10].

If you haven’t thought about COVID-19 enough, the latest pandemic exemplifies the ways in which increasing viral transmission in a warmed and urban climate may indirectly impact the dengue burden. Co-infections, lack of discrimination between COVID-19 and DENV in both clinical presentations and diagnostic methods, as well as access to healthcare may overrun such systems and put patients at further risk [14]. Communities vulnerable to such consequences of global warming and rapid urbanisation reinforces the need to explore beyond purely biological solutions.

Dengue is considered as one of the fastest growing viral diseases today, now extending beyond endemic boundaries consequential to urbanisation and global warming [4]. Vector control methods using Wolbachia bacteria is a promising area of research. However, unresolved consensus on the mechanisms of DENV control leaves more research to be done. Not only is Wolbachia potentially protective against dengue, but also for other diseases including malaria, yellow fever, and zika. Wolbachia is thus a significant bacterium that may potentially lead the fight against mosquito-borne disease for the protection of human health over the coming years.