Differential Immune Responses of Th1 Stimulatory Chimeric Antigens of in BALB/c Mice.

Visceral leishmaniasis (VL) is the third most severe infectious parasitic disease and is caused by the protozoan parasite . To control the spread of the disease in endemic areas where the asymptomatic patients act as reservoirs as well as in nonendemic areas, an effective vaccine is indispensable. In this direction, we have developed three chimeric proteins by the combination of three already known Th1 stimulatory leishmanial antigens, i.

A Plasmodium late liver stage arresting GAP provides superior protection in mice.

Liver-stage genetically attenuated malaria parasites (GAPs) are powerful immunogens that provide protection against sporozoite challenge. We previously generated two late liver-stage-arresting GAPs by deleting the stearoyl-CoA desaturase (Scd) or sporozoite conserved orthologous transcript 1 (Scot1) genes in Plasmodium berghei. Immunization with Scd or Scot1 GAP conferred complete protection against a sporozoite challenge.

ORMDL3 regulates NLRP3 inflammasome activation by maintaining ER-mitochondria contacts in human macrophages and dictates ulcerative colitis patient outcome.

Genome-wide association studies in inflammatory bowel disease have identified risk loci in the orosomucoid-like protein 3/ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) gene to confer susceptibility to ulcerative colitis (UC), but the underlying functional relevance remains unexplored. Here, we found that a subpopulation of the UC patients who had higher disease activity shows enhanced expression of ORMDL3 compared to the patients with lower disease activity and the non-UC controls. We also found that the patients showing high ORMDL3 mRNA expression have elevated interleukin-1β cytokine levels indicating positive correlation.

Antileishmanial evaluation of triazole-butenolide conjugates: design, synthesis, screening, SAR and ADME predictions.

In the quest to discover novel scaffolds with leishmanicidal effects, a series of 23 compounds containing the most promising 1,2,3-triazole and highly potent butenolide in one framework were synthesized. The synthesized conjugates were screened against parasite; five of them showed moderate antileishmanial activity against promastigotes (IC 30.6 to 35.

CLUH functions as a negative regulator of inflammation in human macrophages and determines ulcerative colitis pathogenesis.

Altered mitochondrial function without a well-defined cause has been documented in patients with ulcerative colitis (UC). In our efforts to understand UC pathogenesis, we observed reduced expression of clustered mitochondrial homolog (CLUH) only in the active UC tissues compared with the unaffected areas from the same patient and healthy controls. Stimulation with bacterial Toll-like receptor (TLR) ligands similarly reduced CLUH expression in human primary macrophages.

Immunophenotypic and Functional Characterization of Eosinophil and Migratory Dendritic Cell Subsets during Filarial Manifestation of Tropical Pulmonary Eosinophilia.

The role of eosinophil and migratory dendritic cell (migDC) subsets during tropical pulmonary eosinophilia (TPE), a potentially fatal complication of lymphatic filariasis, has not been explored. We show that the onset of TPE is characterized by the accumulation of ROS and anaphylatoxins and a rapid influx of morphologically distinct Siglec-F resident eosinophils (rEos) and Siglec-F inflammatory eosinophils (iEos) in the lungs, BAL fluid, and blood of TPE mice. While rEos display regulatory behavior, iEos are highly inflammatory cells, as evident in upregulated expression of activation markers CD69 and CD101, anaphylatoxin receptor C5AR1, alarmins s100a8 and s100a9, components of NADPH oxidase, and copious secretion of TNF-α, IFN-γ, IL-6, IL-1β, IL-4, IL-10, IL-12, and TGF-β.

A machine learning-based approach to determine infection status in recipients of BBV152 (Covaxin) whole-virion inactivated SARS-CoV-2 vaccine for serological surveys.

Data science has been an invaluable part of the COVID-19 pandemic response with multiple applications, ranging from tracking viral evolution to understanding the vaccine effectiveness. Asymptomatic breakthrough infections have been a major problem in assessing vaccine effectiveness in populations globally. Serological discrimination of vaccine response from infection has so far been limited to Spike protein vaccines since whole virion vaccines generate antibodies against all the viral proteins.

Biochemical characterization of Recombinase A from Wolbachia endosymbiont of filarial nematode Brugia malayi (wBmRecA).

Lymphatic filariasis is a debilitating disease that affects over 890 million people in 49 countries. A lack of vaccines, non-availability of adulticidal drugs, the threat of emerging drug resistance against available chemotherapeutics and an incomplete understanding of the immunobiology of the disease have sustained the problem. Characterization of Wolbachia proteins, the bacterial endosymbiont which helps in the growth and development of filarial worms, regulates fecundity in female worms and mediates immunopathogenesis of Lymphatic Filariasis, is an important approach to gain insights into the immunopathogenesis of the disease.

Insights from a Pan India Sero-Epidemiological survey (Phenome-India Cohort) for SARS-CoV2.

To understand the spread of SARS-CoV2, in August and September 2020, the Council of Scientific and Industrial Research (India) conducted a serosurvey across its constituent laboratories and centers across India. Of 10,427 volunteers, 1058 (10.14%) tested positive for SARS-CoV2 anti-nucleocapsid (anti-NC) antibodies, 95% of which had surrogate neutralization activity.

Immunization with Calreticulin Protein Generates Robust Antiparasitic Immunity and Offers Protection during Experimental Lymphatic Filariasis.

Lymphatic filariasis causes permanent and long-term disability worldwide. Lack of potent adulticidal drugs, the emergence of drug resistance, and the nonavailability of effective vaccines are the major drawbacks toward LF elimination. However, immunomodulatory proteins present in the parasite secretome are capable of providing good protection against LF and thus offer hope in designing new vaccines against LF.

Immunological characterization of chimeras of high specificity antigens from Mycobacterium tuberculosis H37Rv.

Tuberculosis remains a serious global health problem. BCG is the only prophylactic TB vaccine and it shows variable protective efficacy. Chimeric protein subunit vaccines hold great potential as stand-alone vaccines or heterologous BCG prime boosters.

Acidic Calcium-Independent Phospholipase A2 Regulates Eosinophil-Mediated Pathology during Filarial Manifestation of Tropical Pulmonary Eosinophilia.

Eosinophils mediate pathological manifestations during tropical pulmonary eosinophilia (TPE), a potentially fatal complication of lymphatic filariasis, by mechanisms that are incompletely understood. Using two-dimensional gel electrophoresis, mass spectrometry, flow cytometry, and pharmacological and functional studies, we identified acidic calcium-independent phospholipase A2 (aiPLA2) as the master regulator of TPE pathogenesis. FACS-sorted lung eosinophils from TPE mice exhibited aiPLA2-dependent activation characterized by heavy calcium influx, F-actin polymerization, increased degranulation, and heightened reactive oxygen species generation.

Reciprocal changes in CD11cCD11b and CD11cCD8α dendritic cell subsets determine protective or permissive immune response in murine experimental VL.

CD11cCD8α and CD11cCD11b dendritic cells are two major subsets of murine splenic CD11c DCs which play a crucial role in T cell priming and shaping Th1/Th2 responses, but their role in the context of experimental visceral leishmaniasis (VL) is poorly understood. Herein, we showed that L. donovani infection in Balb/c mice preferentially decreased the population abundance of CD11cCD11b DCs and increased relative abundance of splenic CD11cCD8α DCs.

In Vitro and In Silico Studies of Glycyrrhetinic Acid Derivatives as Anti- Filarial Agents.

Background: Lymphatic filariasis is one of the chronic diseases in many parts of the tropics and sub-tropics of the world despite the use of standard drugs diethylcarbamazine and ivermectin because they kill microfilaries and not the adult parasites. Therefore, new leads with activity on adult parasites are highly desirable.

Objective: Anti-filarial lead optimization by semi-synthetic modification of glycyrrhetinic acid (GA).

Immunogenicity and protective efficacy of Recombinase A from Wolbachia endosymbiont of filarial nematode Brugia malayi (wBmRecA).

Lymphatic filariasis causes global morbidity. Wolbachia, an endo-symbiotic intracellular bacterium of the filarial nematode helps in their growth and development, regulates fecundity in female worms and contributes to the immunopathogenesis of the disease. However, genes and proteins of Wolbachia that may act as putative vaccine candidates are not known.

Infective Larvae of Induce Polarization of Host Macrophages that Helps in Immune Evasion.

Filarial parasites suppress, divert, or polarize the host immune response to aid their survival. However, mechanisms that govern the polarization of host MΦs during early filarial infection are not completely understood. In this study, we infected BALB/c mice with infective larvae stage-3 of (Bm-L3) and studied their effect on the polarization of splenic MΦs.

In vivo neutralization of α4 and β7 integrins inhibits eosinophil trafficking and prevents lung injury during tropical pulmonary eosinophilia in mice.

Integrins regulate leukocyte trafficking during homeostasis and inflammatory conditions. However, the role of α4 and β7 integrins in guiding eosinophil transmigration into the lungs during filarial manifestation of Tropical Pulmonary Eosinophilia (TPE) has not been explored. In this study, mice exhibiting TPE manifestations were administered with in vivo neutralizing antibodies against integrins α4 and β7 or their combination and immuno-pathological parameters were evaluated.

Functional Impairment of Murine Dendritic Cell Subsets following Infection with Infective Larval Stage 3 of Brugia malayi.

Filarial parasites cause functional impairment of host dendritic cells (DCs). However, the effects of early infection on individual DC subsets are not known. In this study, we infected BALB/c mice with infective stage 3 larvae of the lymphatic filarial parasite Brugia malayi (Bm-L3) and studied the effect on fluorescence-activated cell sorter (FACS)-sorted DC subsets.

Characterization of culture filtrate proteins Rv1197 and Rv1198 of ESAT-6 family from Mycobacterium tuberculosis H37Rv.

Background: We have characterized two immunogenic proteins, Rv1197 and Rv1198, of the Esx-5 system of the ESAT-6 family of Mycobacterium tuberculosis H37Rv.

Methods: The complex formation between Rv1197 and Rv1198 was characterized by biophysical techniques. The reactivity of serum from TB patients towards these proteins was characterized by ELISA.

Overcoming drug resistance for macro parasites.

Helminth infections impose burden on human and livestock populations, and their control predominantly relies on periodic mass administration of anthelmintic drugs. However, recent emergence of drug resistance among parasites to currently available drugs raises serious problems for continuation of control strategies and achievement of elimination of parasitic diseases. This review discusses the problem of anthelmintic resistance in humans and livestock, and suggests steps that can be taken to overcome this problem.

Regulatory T-cell neutralization in mice during filariasis helps in parasite clearance by enhancing T helper type 17-mediated pro-inflammatory response.

Lymphatic filariasis leads to profound impairment of parasite-specific T helper type 1 (Th1) and Th2 immune responses and significantly increases the expression of regulatory networks and regulatory effectors like transforming growth factor-β, CD25, cytotoxic T-lymphocyte antigen 4, glucocorticoid-induced tumour necrosis factor receptor (GITR) and regulatory T (Treg) cells, which together play an important role in immunosuppression. While Treg cells suppress the activity of effector cells, monocyte dysfunction, characterized by an alternatively activated immunoregulatory phenotype, is one hypothesis that explains the lack of an antigen-specific T-cell response in infected individuals. In the present study, we administered neutralizing antibodies against the Treg cell-associated markers CD25 and GITR and observed its effects on filaria-induced immunosuppression.

Host lung immunity is severely compromised during tropical pulmonary eosinophilia: role of lung eosinophils and macrophages.

Eosinophils play a central role in the pathogenesis of tropical pulmonary eosinophilia, a rare, but fatal, manifestation of filariasis. However, no exhaustive study has been done to identify the genes and proteins of eosinophils involved in the pathogenesis of tropical pulmonary eosinophilia. In the present study, we established a mouse model of tropical pulmonary eosinophilia that mimicked filarial manifestations of human tropical pulmonary eosinophilia pathogenesis and used flow cytometry-assisted cell sorting and real-time RT-PCR to study the gene expression profile of flow-sorted, lung eosinophils and lung macrophages during tropical pulmonary eosinophilia pathogenesis.

Host immune response is severely compromised during lethal Plasmodium vinckei infection.

Cytokines and immune effector cells play an important role in determining the outcome of infection with various intracellular pathogens, including protozoan parasites. However, their role during lethal and nonlethal malaria needs further validation. In the present study, we examined the role of cytokines and various immune effector cells during lethal and nonlethal malaria caused by Plasmodium vinckei in AKR mice.

Combination of liposomal CpG oligodeoxynucleotide 2006 and miltefosine induces strong cell-mediated immunity during experimental visceral leishmaniasis.

Immuno-modulators in combination with antileishmanial drug miltefosine is a better therapeutic approach for treatment of Visceral Leishmaniasis (VL) as it not only reduces the dose of miltefosine but also shortens the treatment regimen. However, immunological mechanisms behind the perceived benefits of this combination therapy have not been investigated in detail. In the present study, we hypothesized that potential use of drugs that target the host in addition to the parasite might represent an alternative strategy for combination therapy.