Innate immunity to filarial parasites initiates and maintains the adaptive immune response
Open AccessFilarial nematodes infect ~170 million people worldwide and are the causative agents of the diseases lymphatic filariasis, onchocerciasis (river blindness), loaisis, and mansonellosis. These diseases represent some of the leading causes of disability worldwide, thus making them of critical public health importance. Understanding of the immunological responses to these parasites is important not only for developing effective treatments and interventions, but also to gain a better understanding of parasite survival and pathogenesis of disease. Two of the hallmarks of adaptive immunity in filariasis are hyporesponsiveness of CD4+ T cells to filarial antigen and the skewing of T cell differentiation toward Th2 and Th17 subsets. Since it is likely that the innate immune response to filarial parasites sets up the characteristic adaptive response seen in filarial parasite infection, we investigated the role of the innate immune system in influencing the Th subset distribution and the T cell hyporesponsiveness seen in filarial infection. Dysfunctional antigen presenting cells (APC) represent one mechanism by which T cell becomes unable to respond to filarial antigen in chronic infection and this dysfunction may start at the earliest stages of the infection when the invading third-stage larvae (L3) encounters skin-dwelling LC and keratinocytes (KC). After exposure to L3, in vitro generated LC showed no alterations in cell surface marker expression, nor in the mRNA expression or protein production of inflammation-associated cytokines. In contrast, live T. gondii, induced production of CXCL9, CXCL10, and IL-6 in LC. Interestingly, exposure of the co-cultures (LC/KC) to live L3 did not result in altered cytokine production. Microarray examination of ex vivo LC exposed to live L3 also showed few significant changes in gene expression. Our data suggest that failure by LC to initiate a response to the invasive stage of filarial parasites may contribute to the hyporesponsiveness seen later in the infection. The cells and molecules responsible for the expansion of T cell subsets (Th2 and Th17) in filarial infection have yet to be defined. Recently identified, innate lymphoid cells (ILCs) are a new family of innate cells, which play a role in the differentiation of T cells to various subsets. To gain a fuller understanding of the function of these cells, ILCs were purified from normal blood and shown to produce large amounts of cytokines in response to stimulation. RNAseq analysis of ILCs showed a wide range of immunologically relevant transcripts upregulation of transcripts associated with proliferation as well downregulation of transcripts associated with chemotaxis. The immunological relevance of these ILCs in helminth infection was demonstrated by two-fold expansion of these cells in filarial infection of humans and a significant relationship between the numbers of ILCs and the number of IL-17 producing CD4+ T cells. To further confirm the role of ILCs in filarial infection, Balb/c mice were infected with the rodent filarial parasite, Litomosoides sigmodontis and the presence of ILC subpopulations, multipotent progenitor cells (MPPs) and ILC2s were verified by multi-color flow cytometry. MPPs and ILC2s were increased in the pleural cavity around the time of patency, although this increase was not seen systemically. In addition, markers of Th2 immunity, both locally and systemically, occurred at the time the mice became microfilaremic. The timing of expansion in MPPs and ILC2s and the expansion of the Th2 response around the time of patency suggests a role of these cells in the polarization of the immune system towards a Th2 type response. Taken together, these data highlight pathways by which the innate immune response to filarial parasites influence the subsequent adaptive response at the initial stages of the infection, by dampening the LC reaction to the invading parasite and polarizing the immune system towards a Th2 response. The innate immune system continues to provide signals to the adaptive immune systems throughout the course of infection as ILCs in infected individuals correlated with the Th17 subset of CD4+ T cells in these individuals. These filarial-specific immunological pathways may provide mechanisms of immune evasion for the parasite, allowing it to persist in the host for years.
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Boyd_gwu_0075A_12001.pdf | 2018-01-16 | Open Access |
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Appendix1.pdf | 2018-01-16 | Open Access |
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