Protective role of complement factor H against the development of preeclampsia.

Pregnancy is an immunologically regulated, complex process. A tightly controlled complement system plays a crucial role in the successful establishment of pregnancy and parturition. Complement inhibitors at the feto-maternal interface are likely to prevent inappropriate complement activation to protect the fetus. In the present study, we aimed to understand the role of Factor H (FH), a negative regulator of complement activation, in normal pregnancy and in a model of pathological pregnancy, i.e. preeclampsia (PE). The distribution and expression of FH was investigated in placental tissues, various placental cells, and in the sera of healthy (CTRL) or PE pregnant women via immunohistochemistry, RT-qPCR, ELISA, and Western blot. Our results showed a differential expression of FH among the placental cell types, decidual stromal cells (DSCs), decidual endothelial cells (DECs), and extravillous trophoblasts (EVTs). Interestingly, FH was found to be considerably less expressed in the placental tissues of PE patients compared to normal placental tissue both at mRNA and protein levels. Similar results were obtained by measuring circulating FH levels in the sera of third trimester CTRL and PE mothers. Syncytiotrophoblast microvesicles, isolated from the placental tissues of PE and CTRL women, downregulated FH expression by DECs. The present study appears to suggest that FH is ubiquitously present in the normal placenta and plays a homeostatic role during pregnancy.

Anti-Spike Antibodies Present in the Milk of SARS-CoV-2 Vaccinated Mothers Are Complement-Activating.

Although only 0.8-1% of SARS-CoV-2 infections are in the 0-9 age-group, pneumonia is still the leading cause of infant mortality globally. Antibodies specifically directed against SARS-CoV-2 spike protein (S) are produced during severe COVID-19 manifestations. Following vaccination, specific antibodies are also detected in the milk of breastfeeding mothers. Since antibody binding to viral antigens can trigger activation of the complement classical - pathway, we investigated antibody-dependent complement activation by anti-S immunoglobulins (Igs) present in breast milk following SARS-CoV-2 vaccination. This was in view of the fact that complement could play a fundamentally protective role against SARS-CoV-2 infection in newborns. Thus, 22 vaccinated, lactating healthcare and school workers were enrolled, and a sample of serum and milk was collected from each woman. We first tested for the presence of anti-S IgG and IgA in serum and milk of breastfeeding women by ELISA. We then measured the concentration of the first subcomponents of the three complement pathways (i.e., C1q, MBL, and C3) and the ability of anti-S Igs detected in milk to activate the complement in vitro. The current study demonstrated that vaccinated mothers have anti-S IgG in serum as well as in breast milk, which is capable of activating complement and may confer a protective benefit to breastfed newborns.

Pathogenesis and Host Immune Response in Leprosy.

Leprosy is an ancient insidious disease caused by Mycobacterium leprae, where the skin and peripheral nerves undergo chronic granulomatous infections, leading to sensory and motor impairment with characteristic deformities. Susceptibility to leprosy and its disease state are determined by the manifestation of innate immune resistance mediated by cells of monocyte lineage. Due to insufficient innate resistance, granulomatous infection is established, influencing the specific cellular immunity. The clinical presentation of leprosy ranges between two stable polar forms (tuberculoid to lepromatous) and three unstable borderline forms. The tuberculoid form involves Th1 response, characterized by a well demarcated granuloma, infiltrated by CD4+ T lymphocytes, containing epitheloid and multinucleated giant cells. In the lepromatous leprosy, there is no characteristic granuloma but only unstructured accumulation of ineffective macrophages containing engulfed pathogens. Th1 response, characterised by IFN-γ and IL-2 production, activates macrophages in order to kill intracellular pathogens. Conversely, a Th2 response, characterized by the production of IL-4, IL-5 and IL-10, helps in antibody production and consequently downregulates the cell-mediated immunity induced by the Th1 response. M. lepare has a long generation time and its inability to grow in culture under laboratory conditions makes its study challenging. The nine-banded armadillo still remains the best clinical and immunological model to study host-pathogen interaction in leprosy. In this chapter, we present cellular morphology and the genomic uniqueness of M. leprae, and how the pathogen shows tropism for Schwann cells, macrophages and dendritic cells.

Innate Immune Response Against HIV-1.

The innate immune system is comprised of both cellular and humoral players that recognise and eradicate invading pathogens. Therefore, the interplay between retroviruses and innate immunity has emerged as an important component of viral pathogenesis. HIV-1 infection in humans that results in hematologic abnormalities and immune suppression is well represented by changes in the CD4/CD8 T cell ratio and consequent cell death causing CD4 lymphopenia. The innate immune responses by mucosal barriers such as complement, DCs, macrophages, and NK cells as well as cytokine/chemokine profiles attain great importance in acute HIV-1 infection, and thus, prevent mucosal capture and transmission of HIV-1. Conversely, HIV-1 has evolved to overcome innate immune responses through RNA-mediated rapid mutations, pathogen-associated molecular patterns (PAMPs) modification, down-regulation of NK cell activity and complement receptors, resulting in increased secretion of inflammatory factors. Consequently, epithelial tissues lining up female reproductive tract express innate immune sensors including anti-microbial peptides responsible for forming primary barriers and have displayed an effective potent anti-HIV activity during phase I/II clinical trials.

Vaccination Strategies Against Mycobacterium tuberculosis: BCG and Beyond.

Tuberculosis (TB) is a highly contagious disease caused by Mycobacterium tuberculosis (Mtb) and is the major cause of morbidity and mortality across the globe. The clinical outcome of TB infection and susceptibility varies among individuals and even among different populations, contributed by host genetic factors such as polymorphism in the human leukocyte antigen (HLA) alleles as well as in cytokine genes, nutritional differences between populations, immunometabolism, and other environmental factors. Till now, BCG is the only vaccine available to prevent TB but the protection rendered by BCG against pulmonary TB is not uniform. To deliver a vaccine which can give consistent protection against TB is a great challenge with rising burden of drug-resistant TB. Thus, expectations are quite high with new generation vaccines that will improve the efficiency of BCG without showing any discordance for all forms of TB, effective for individual of all ages in all parts of the world. In order to enhance or improve the efficacy of BCG, different strategies are being implemented by considering the immunogenicity of various Mtb virulence factors as well as of the recombinant strains, co-administration with adjuvants and use of appropriate vehicle for delivery. This chapter discusses several such pre-clinical attempts to boost BCG with subunit vaccines tested in murine models and also highlights various recombinant TB vaccines undergoing clinical trials. Promising candidates include new generation of live recombinant BCG (rBCG) vaccines, VPM1002, which are deleted in one or two virulence genes. They encode for the mycobacteria-infected macrophage-inhibitor proteins of host macrophage apoptosis and autophagy, key events in killing and eradication of Mtb. These vaccines are rBCG- ΔureC::hly HMR, and rBCG-ΔureC::hly ΔnuoG. The former vaccine has passed phase IIb in clinical trials involving South African infants and adults. Thus, with an aim of elimination of TB by 2050, all these cumulative efforts to develop a better TB vaccine possibly is new hope for positive outcomes.

Immune Responses in Malaria and Vaccine Strategies.

Malaria is a pandemic with nearly half of global population at risk, caused by parasite Plasmodium species, particularly P. falciparum with a high morbidity and mortality, especially among children. There is an urgent need for development of population protective vaccines, such as in sub-Saharan low-income countries, where P. falciparum malaria is endemic. After years of endeavour with children and adults for safety and efficacy clinical trials, the P. falciparum circumsporozoite protein antigen, is targeted by specific antibodies induced by recombinant vaccine, called TRS,S. TRS,S has been authorized by WHO and Malawi Government to be the first malaria vaccine for up to 2 years of aged children for protection against malaria. Other malaria vaccines in clinical trials are also very promising candidates, including the original live, X-ray attenuated P-sporozoite vaccine, inducing antigen-specific T cell immunity at liver stage. Malaria parasite at blood symptomatic stage is targeted by specific antibodies to parasite-infected erythrocytes, which are important against pathogenic placenta-infected erythrocyte sequestration. Here, the demographic distribution of Plasmodium species and their pathogenicity in infected people are discussed. The role of innate phagocytic cells and malaria antigen specific T cell immunity, as well as that of specific antibody production by B cells are highlighted. The paramount role of cytotoxic CD8+ T cellular immunity in malaria people protection is also included.

SARS-CoV-2: Pathogenic Mechanisms and Host Immune Response.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped, positive-sense RNA coronavirus responsible for the COVID-19 pandemic. Since December 2019, coronavirus disease 2019 (COVID-19) has affected more than 127 million people, 2.7 million deaths globally (as per WHO dashboard, dated 31 March, 2020), the virus is capable of transmitting from human to human via inhalation of infected respiratory droplets or aerosols or contact with infected fomites. Clinically, patients with COVID-19 present with severe respiratory distress syndrome, which is very similar to the presentation of other respiratory viral infections. A huge variation in the host response exists, with the resulting symptoms varying from mild to moderate. Comorbidities such as cardiovascular disease, hypertension, diabetes, coagulation dysfunction, stroke, malignant tumor and multiple organ dysfunction syndrome, as well as age and sex, are associated with severe COVID-19 cases. So far, no targeted therapies have been developed to treat this disease and existing drugs are being investigated for repurposing. This chapter discusses the epidemiology, clinical features of COVID-19, pathogenesis and the innate and adaptive immune response mounted by the host to the SARS-CoV-2 infection. A deeper understanding of the host-pathogen interaction is fundamental to the development of a vaccine.

Host-pathogen interaction in COVID-19: Pathogenesis, potential therapeutics and vaccination strategies.

The current coronavirus pandemic, COVID-19, is the third outbreak of disease caused by the coronavirus family, after Severe Acute Respiratory Syndrome and Middle East Respiratory Syndrome. It is an acute infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This severe disease is characterised by acute respiratory distress syndrome, septic shock, metabolic acidosis, coagulation dysfunction, and multiple organ dysfunction syndromes. Currently, no drugs or vaccines exist against the disease and the only course of treatment is symptom management involving mechanical ventilation, immune suppressants, and repurposed drugs. The severe form of the disease has a relatively high mortality rate. The last six months have seen an explosion of information related to the host receptors, virus transmission, virus structure-function relationships, pathophysiology, co-morbidities, immune response, treatment and the most promising vaccines. This review takes a critically comprehensive look at various aspects of the host-pathogen interaction in COVID-19. We examine the genomic aspects of SARS-CoV-2, modulation of innate and adaptive immunity, complement-triggered microangiopathy, and host transmission modalities. We also examine its pathophysiological impact during pregnancy, in addition to emphasizing various gaps in our knowledge. The lessons learnt from various clinical trials involving repurposed drugs have been summarised. We also highlight the rationale and likely success of the most promising vaccine candidates.

Molecular Heterogeneity and Immunosuppressive Microenvironment in Glioblastoma.

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with a poor prognosis, despite surgical resection combined with radio- and chemotherapy. The major clinical obstacles contributing to poor GBM prognosis are late diagnosis, diffuse infiltration, pseudo-palisading necrosis, microvascular proliferation, and resistance to conventional therapy. These challenges are further compounded by extensive inter- and intra-tumor heterogeneity and the dynamic plasticity of GBM cells. The complex heterogeneous nature of GBM cells is facilitated by the local inflammatory tumor microenvironment, which mostly induces tumor aggressiveness and drug resistance. An immunosuppressive tumor microenvironment of GBM provides multiple pathways for tumor immune evasion. Infiltrating immune cells, mostly tumor-associated macrophages, comprise much of the non-neoplastic population in GBM. Further understanding of the immune microenvironment of GBM is essential to make advances in the development of immunotherapeutics. Recently, whole-genome sequencing, epigenomics and transcriptional profiling have significantly helped improve the prognostic and therapeutic outcomes of GBM patients. Here, we discuss recent genomic advances, the role of innate and adaptive immune mechanisms, and the presence of an established immunosuppressive GBM microenvironment that suppresses and/or prevents the anti-tumor host response.

Natural and trained innate immunity against Mycobacterium tuberculosis.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) infection, remains a major global health emergency. It is estimated that one third of global population are affected, predominantly with latent granuloma form of the disease. Mtb co-evolved with humans, for its obligatory intra-macrophage phagosome habitat and slow replication, balanced against unique mycobacterial innate immunity, which appears to be highly complex. TB is transmitted via cough aerosol Mtb inhalation. Bovine TB attenuated Bacillus Calmette Guerin (BCG) live vaccine has been in practice for protection of young children from severe disseminated Mtb infection, but not sufficiently for their lungs, as obtained by trials in TB endemic community. To augment BCG vaccine-driven innate and adaptive immunity for neonates and better protection against adult pulmonary TB, a number of BCG pre-vaccination based, subset vaccine candidates have been tested via animal preclinical, followed by safe clinical trials. BCG also enhances innate macrophage trained immunity and memory, through primordial intracellular Toll-like receptors (TLRs) 7 and 9, which recognise distinct mycobacterial molecular pattern signature. This signature is transmitted by TLR signalling via nuclear factor-κB, for activating innate immune transcription and expression of gene profiling in a mycobacterial signature-specific manner. These are epigenetically imprinted in reprogramming of distinct chromatin areas for innate immune memory, to be recalled following lung reinfection. Unique TB innate immunity and its trained memory are considered independent from adaptive immune B and T cells. On the other hand, adaptive immunity is crucial in Mtb containment in granulomatous latency, supported by innate immune cell infiltration. In nearly 5-10 % of susceptible people, latent TB may be activated due to immune evasion by Mtb from intracellular phagosome within macrophage, perpetrating TB. However, BCG and new recombinant BCG vaccines have the capacity, as indicated in pre- and clinical trials, to overcome such Mtb evasion. Various strategies include pro-inflammatory-bactericidal type 1 polarisation (M1) phenotype of the infected macrophage, involving thrombospondin-TLR pathway. Saprophytic M. smegmatis-based recombinant vaccines are also promising candidates against TB. BCG vaccination of neonates/infants in TB endemic countries also reduced their pneumonia caused by various microbes independent of TB immunity. Here, we discuss host immune response against Mtb, its immune evasion strategies, and the important role innate immunity plays in the development of protection against TB.

Alcoholic turmeric extract simultaneously activating murine lymphocytes and inducing apoptosis of Ehlrich ascitic carcinoma cells.

In the present investigation ethanolic turmeric extract has been found to play diabolically opposite role on murine lymphocytes and on Ehlrich ascitic carcinoma cells. Turmeric stimulates the lymphocytes into the effector pathway as studied through in vitro viability, blastogenesis and (3)H-TdR incorporation and also seems to be healthy under scanning electron microscopy (SEM). SEM revealed the formation of cytoplasmic blebs and plasma membrane disintegration of tumor cells with ethanolic turmeric extract treatment, suggesting turmeric to be initiating apoptosis of tumor cells. Thus, in the present work viability of the cells, blastogenesis, DNA synthesis and SEM study establish the fact that turmeric is a conducive agent for lymphocytes and inhibitory as well as apoptotic for tumor cells.