RecombinantWolbachia surface protein (WSP)-induced T cell responses in Wuchereria bancrofti infections

Human lymphatic filariasis is a debilitating parasitic disease characterized by downregulation of the host’s immune response in asymptomatic carriers along with profound hyperreactivity in chronic patients apart from putatively immune endemic normals. The endosymbiont Wolbachia, a bacterium of filarial nematodes has received much attention as possible chemotherapeutic target and its involvement in disease pathogenesis. The role of recombinant Wolbachia surface protein (rWSP), one of the most abundantly expressed proteins of the endosymbiont, in modulating cell-mediated immune responses in patients harboring Wuchereria bancrofti infections was evaluated in the current study. rWSP-induced lymphoproliferation with peripheral blood mononuclear cells suggested an impaired proliferative response in asymptomatic microfilaremic (MF) and symptomatic chronic pathology (CP) patients compared to endemic normals (EN). This was further supported by a significantly diminished expression of CD69 along with elevated levels of CD127 and CD62L in filarial patients (MF and CP) compared to EN. Further, rWSP induced the expression of regulatory T cell markers CTLA-4 and CD25 along with suppressor cytokines IL-10 and TGF-β in MF and CP patients compared to EN. However, the rWSP-stimulated expression of IFN-γ was diminished significantly in filarial patients compared to endemic normals. Thus, these findings suggest that WSP may also contribute to the suppression of immune responses seen in filarial patients

Autophagy Protects Monocytes from Wolbachia Heat Shock Protein 60–Induced Apoptosis and Senescence

Monocyte dysfunction by filarial antigens has been a major mechanism underlying immune evasion following hyporesponsiveness during patent lymphatic filariasis. Recent studies have initiated a paradigm shift to comprehend the immunological interactions of Wolbachia and its antigens in inflammation, apoptosis, lymphocyte anergy, etc. Here we showed that recombinant Wolbachia heat shock protein 60 (rWmhsp60) interacts with TLR-4 and induces apoptosis in monocytes of endemic normal but not in chronic patients. Higher levels of reactive oxygen species (ROS) induced after TLR-4 stimulation resulted in loss of mitochondrial membrane potential and caspase cascade activation, which are the plausible reason for apoptosis. Furthermore, release in ROS owing to TLR-4 signaling resulted in the activation of NF-κB p65 nuclear translocation which leads to inflammation and apoptosis via TNF receptor pathway following the increase in IL-6 and TNF-α level. Here for the first time, we report that in addition to apoptosis, rWmhsp60 antigen in filarial pathogenesis also induces molecular senescence in monocytes. Targeting TLR-4, therefore, presents a promising candidate for treating rWmhsp60-induced apoptosis and senescence. Strikingly, induction of autophagy by rapamycin detains TLR-4 in late endosomes and subverts TLR-4-rWmhsp60 interaction, thus protecting TLR-4-mediated apoptosis and senescence. Furthermore, rapamycin-induced monocytes were unresponsive to rWmhsp60, and activated lymphocytes following PHA stimulation. This study demonstrates that autophagy mediates the degradation of TLR-4 signaling and protects monocytes from rWmhsp60 induced apoptosis and senescence

Avian Influenza Virus

Avian influenza is a disease caused by influenza A virus (IAV) that mainly affects domestic poultry but poses a serious zoonotic threat due to direct transmission from poultry to mammals including human beings. While the high pathogenic avian influenza (HPAI) mainly caused by H5 and H7 subtypes of IAVs lead to high mortality, the low pathogenic avian influenza (LPAI) caused by all the 16 haemagglutinin subtypes lead to high production losses. Wild aquatic birds serve as reservoir hosts as the virus cause productive subclinical infections in them. Reported for the first time in 1878 in Italy, the IAVs have so far caused three pandemics in humans. The H5N1 virus currently circulating for over two decades throughout the world has caused outbreaks in over 60 countries including India. LPAI viruses are transmitted amongst terrestrial poultry via respiratory droplets and aerosols and the HPAI viruses are transmitted via faecal route. Pathogenesis of IAVs is markedly different between wild water birds, terrestrial poultry and humans. Clinical diagnosis of AI is very difficult and often confused with other respiratory diseases of poultry. Diagnosis of AI involves isolation, identification and characterization of the virus. Current molecular techniques particularly the RT-PCR and real-time RT-PCR are recommended for rapid AI diagnosis. Effective control programs for avian influenza in poultry farms or its spread between farms can reduce the loss due to the disease by a minimum of 75%. The various control measures along with their advantages and disadvantages are discussed in detail in this chapter