Transcriptomics and Immune Profiles of Asymptomatic Filarial-Infected Individuals

Abstract

Filarial infections caused by <i>Wuchereria bancrofti</i> and <i>Brugia</i> species (lymphatic filariasis (LF)) and <i>Onchocerca volvulus</i> (onchocerciasis) affect almost 200 million individuals worldwide and pose major public health challenges in endemic regions. Indeed, the collective DALYs (disability-adjusted life years) for both infections is 3.3 million. Infections with these thread-like nematodes are chronic and although most individuals develop a regulated state, a portion develop severe forms of pathology. Mass drug administration (MDA) programmes on endemic populations focus on reducing prevalence levels of people with microfilariae (MF), the worm's offspring in the blood to less than 1%. Although this has been successful in some areas, studies show that MDA will be required for longer than initially conceived. Thus, there is still a requirement for better drugs or vaccines. <i>W. bancrofti</i>-infected individuals without pathology (asymptomatic) can be subdivided into two groups that are patent (MF+) or latent (MF-). Patent infections are associated with an immunologically tolerant phenotype state that favours worm survival and in addition does not provoke overt pathology in the host. Latent infections are characterized by the lack of MF in the periphery, despite the presence of adult worms, and their immune profiles show markers of immune-mediated MF control. In <i>O. volvulus</i> infection however, the majority of individuals have dermal-residing MF and amicrofilaridermic (a-MF) individuals appear to be the consequences of repeated MDA treatment. Interestingly, recent research revealed that <i>O. volvulus</i> endemic areas, with a lowered infection pressure due to MDA, appear to influence bystander responses to <i>Plasmodium</i>-derived antigens in community members even if they have not regularly participated in the therapy. Pathology that arises in either filarial infection is associated with dampened regulatory T cell responses (Treg) and IL-10 but elevated Th17 responses. Thus, identifying immune determinants that drive these different infection states has the potential to guide the development of improved anti-filarial drugs and vaccines. In this study, microarray and cellular profiling approaches were used to evaluate gene expression patterns and to reveal genetic pathways specific to <i>W. bancrofti</i> or <i>O. volvulus</i> infection. Individuals with latent LF infections showed an enhanced gene expression profile, including genes involved in Actin Nucleation by ARP-WASP Complex, Rac signaling, Cdc42 signaling, RhoGD1 signaling, eosinophil effector functions and CD28 signaling in T helper cell pathways. Interestingly, the <i>Charcot-Leyden crystal/galectin-10 (CLC/Gal-10)</i>, an immunosuppressive molecule, was among the top commonly expressed genes in both infections and elevated levels were also detected in plasma. Moreover, compared to healthy volunteers, T cells recovered from <i>W. bancrofti</i>-infected individuals secreted higher levels of CLC/Gal-10 and were even higher in MF+ individuals: by complementing their elevated Treg responses (Foxp3/IL-10). Latent <i>W. bancrofti</i>-infected individuals on the other hand had pronounced Th1, Th2 and Th17 responses. With regards to filarial-specific antibody responses, IgG4, IgE and IgA in plasma were associated with MF+, MF- and endemic normals, respectively. Overall, the transcriptome profiling revealed overlapping genes in both infections: <i>CLC/Gal-10</i>, <i>ribonuclease RNase A family, 2 (RNASE2)</i> and <i>ribosomal protein S4, y-linked 1 (RPS4Y1)</i>. Thus, the study offers insight into filarial-specific genes, signaling pathways and immune determinants, which may be central targets towards the development of new anti-filarial interventions.