Scavenger receptors in host defense: from functional aspects to mode of action

Scavenger receptors belong to a superfamily of proteins that are structurally heterogeneous and encompass the miscellaneous group of transmembrane proteins and soluble secretory extracellular domain. They are functionally diverse as they are involved in various disorders and biological pathways and their major function in innate immunity and homeostasis. Numerous scavenger receptors have been discovered so far and are apportioned in various classes (A-L). Scavenger receptors are documented as pattern recognition receptors and known to act in coordination with other co-receptors such as Toll-like receptors in generating the immune responses against a repertoire of ligands such as microbial pathogens, non-self, intracellular and modified self-molecules through various diverse mechanisms like adhesion, endocytosis and phagocytosis etc. Unlike, most of the scavenger receptors discussed below have both membrane and soluble forms that participate in scavenging; the role of a potential scavenging receptor Angiotensin-Converting Enzyme-2 has also been discussed whereby only its soluble form might participate in preventing the pathogen entry and replication, unlike its membrane-bound form. This review majorly gives an insight on the functional aspect of scavenger receptors in host defence and describes their mode of action extensively in various immune pathways involved with each receptor type.

Possible Interference in Protein – Protein interaction as a new approach in microinhibition of respiratory pathogens on nasal– oral epithelium: An early on-screen study with reference toSARS-Cov-2–ACE2 binding interference

Upper and lower respiratory pathogens – both microbes and viruses –are responsible for very high morbidity, man-hour loss, residual long term clinical conditions and even mortality. In india only, high incidence of annual respiratory infections – both UT and LT – demands prophylactic intervention in addition to all therapeutic interventions available.The issue of respiratory infections is more pronounced now in the backdrop of nearly uncontrolled high incidences of SARS-Cov-2 affection resulting in death and damage of human lives to the extent of hundreds of millions spreading over entire world, with incidence variations from country to country. After the initial unanswered phase of spread of SARS-Cov-2 virus with attendant unseen mortalities, quickest invention of a series of unusual vaccines have stemmed the lethal progress to a very significant extent, although vaccinating each and every human subject – nearly 8 to 9 bn in supremely divided world –economically-- is an unthinkable proposition where economic disparity dictates vaccine availability and implementation.Moreover, being of highly unstable nucleic acid composition, the original virus, by now has a thick set of variants around the globe with variable clinical outcome. Given this complex background of scanty availability and inefficient implementation, there always is a need of a preventive approach which can possibly micro-fix the pathogens, including SARS-2 on nasal epithelium so as to interfere with viral [or any pathogen] entry through specified receptor gate[s] or any other ways. The present formulation is under study -- as a candidate of interference on nasal / oral mucosa for all respiratory pathogens. This brief report describes dry on-screen studies of protein – protein interaction as well as its possible interference by an amino acid Lysine. Phospholipid bilayerresponses in presence of added loads of the same essential amino acid –Lysine – showed unusual and unexplained behavior both in structural integrity as well in spatial orientation.

MPK3- and MPK6-mediated VLN3 phosphorylation regulates actin dynamics during stomatal immunity in Arabidopsis

Upon perception of pathogens, plants can rapidly close their stomata to restrict pathogen entry into internal tissue, leading to stomatal immunity as one aspect of innate immune responses. The actin cytoskeleton is required for plant defense against microbial invaders. However, the precise functions of host actin during plant immunity remain largely unknown. Here, we report that Arabidopsis villin3 (VLN3) is critical for plant resistance to bacteria by regulating stomatal immunity. Our in vitro and in vivo phosphorylation assays show that VLN3 is a physiological substrate of two pathogen-responsive mitogen-activated protein kinases, MPK3/6. Quantitative analyses of actin dynamics and genetic studies reveal that VLN3 phosphorylation by MPK3/6 modulates actin remodeling to activate stomatal defense in Arabidopsis.

Mycobacterium Tuberculosis (Tuberculosis)

Tuberculosis (TB) is a major health threat caused by the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb). Globally, 10 million individuals fell ill of TB and 1.4 million died in 2019. The COVID-19 pandemic has severely impacted on TB notifications in 2020, thereby markedly increasing morbidity and mortality caused by TB. The lung is the most frequent site of disease manifestation, the site of pathogen entry and the source of dissemination. In the infected lung, granulomas are formed at the site of Mtb persistence which primarily consist of macrophages of different maturation stages and T lymphocytes. Solid granulomas contain Mtb, thus preventing outbreak of active disease. The individual is now latently infected. Once Mtb evades immune control, granulomas become necrotic and later caseous. Active TB disease has started. Diagnosis of TB is done by chest X-ray, microscopy, bacterial culture, molecular test, and immunologic test. TB can be cured by a combination of 3-4 specific drugs given over a period of 6-9 months. Increasing incidences of multi-drug and extensively drug-resistant Mtb render therapy difficult to impossible. The current vaccine, Bacille Calmette-Guérin (BCG) prevents extrapulmonary childhood TB but fails to protect against pulmonary TB in all age groups. New vaccines against TB are urgently needed. New candidates that have entered clinical trials are killed whole cell vaccines, recombinant live vaccines, Mtb antigen-adjuvant formulations or viral vectors expressing Mtb antigens.

Regulation of invasion-associated actin dynamics by the Chlamydia trachomatis effectors TarP and TmeA

The obligate intracellular pathogen Chlamydia trachomatis manipulates the host actin cytoskeleton to assemble actin-rich structures that drive pathogen entry. This actin remodeling event exhibits relatively rapid dynamics that, through quantitative live-cell imaging, was revealed to consist of three phases – a fast recruitment phase which abruptly transitions to a fast turnover phase before resolving into a slow turnover of actin, indicating the end of actin remodeling. Here, we investigate Chlamydia invasion in the context of actin dynamics. Efficient invasion was associated with robust actin remodeling kinetics, which was linked to signaling from the type-III secreted effectors TarP and TmeA, and the actin nucleating activities of formin 1 (Fmn1) and Arp2/3. Stable recruitment of Fmn1 and Arp2/3 was dependent upon TarP and/or TmeA, although TarP signaling was responsible for the majority of Fmn1 and Arp2/3 recruitment. Rapid actin kinetics were due in part to a collaborative functional interaction between two different classes of actin nucleators – formins, including formin 1 and the diaphanous-related formins mDia1 and mDia2, and the Arp2/3 complex. Inhibition of either formin or Arp2/3, or deletion of TarP and TmeA, prevented this collaboration and resulted in attenuated actin kinetics and invasion efficiency. Collectively, these data support a model wherein TarP and TmeA signaling are core components of actin remodeling that operate via stable recruitment of formin and Arp2/3. At the population level, the kinetics of recruitment and turnover of actin and its nucleators were linked. However, reanalysis of the data at the level of individual elementary bodies showed significant variation and a lack of correlation between the kinetics of recruitment and turnover, suggesting that accessory factors variably modify actin kinetics at individual entry sites. In summary, efficient chlamydial invasion is an effector-driven process that requires a specific profile of actin recruitment which arises following collaboration between formin and Arp2/3.

The Roles of Tissue-Resident Memory T Cells in Lung Diseases

The unique environment of the lungs is protected by complex immune interactions. Human lung tissue-resident memory T cells (TRM) have been shown to position at the pathogen entry points and play an essential role in fighting against viral and bacterial pathogens at the frontline through direct mechanisms and also by orchestrating the adaptive immune system through crosstalk. Recent evidence suggests that TRM cells also play a vital part in slowing down carcinogenesis and preventing the spread of solid tumors. Less beneficially, lung TRM cells can promote pathologic inflammation, causing chronic airway inflammatory changes such as asthma and fibrosis. TRM cells from infiltrating recipient T cells may also mediate allograft immunopathology, hence lung damage in patients after lung transplantations. Several therapeutic strategies targeting TRM cells have been developed. This review will summarize recent advances in understanding the establishment and maintenance of TRM cells in the lung, describe their roles in different lung diseases, and discuss how the TRM cells may guide future immunotherapies targeting infectious diseases, cancers and pathologic immune responses.

Immunopathogenesis of Aspergillosis

Aspergillus species are ubiquitous saprophytes and opportunistic pathogens causing wide spectrum of diseases in humans depending on the host immune status. Following pathogen entry, various soluble bronchopulmonary factors enhance conidial clearance. However, due to virulence factors and poor host immune response Aspergillus conidia bind and damage the airway epithelium. The host immune cells like neutrophils and macrophages recognise Aspergillus spp. through various pathogen recognition receptors and form reactive oxygen species which mediate conidial killing. Neutrophils also attack extracellular hyphae by oxidative attack, non-oxidative granule proteins and neutrophil extracellular traps. In case of adaptive immunity, Th1 cells are crucial sources of IFN-γ mediated protective immunity. The Th17 also display a highly pro-inflammatory which is counterbalanced by a Treg cell. B cells and antibodies also enhance fungal clearance although excessive IgE production may result in atopy. The immune responses are influenced by changes in production of short-chain fatty acids by the gut microbiome which primes cells toward Th2 responses, and this is synchronized by the Innate lymphoid cells. This review provides comprehensive knowledge of various virulence factors of Aspergillus, antifungal host defences including innate and humoral immune response and regulation of host immunity by microbiome.

Implicit, Intrinsic, Extrinsic (or Environmental), and Host Factors Attributing the Covid-19 Pandemic. Part 2- Implicit Factor Pesticide Use: A Systematic Analysis

Advances in our understanding of complex COVID-19 pandemic would allow us to effectively eliminate and eradicate SARS-COV2 virus. Although tremendous amount of research devoted to the robustness across its biology, diagnostics, vaccines and treatment has exploded in the past two years. However, still science do not have robust answers for causes, for example (i) What are the reasons of non-uniform global distribution of COVID-19? (ii) Why the United States, India, and Brazil, are the first-three most affected nations?, (iii) How did Bhutan, a nation sharing a boundary with China manage nearly 0.34% infections and 3 deaths from COVID-19? Nonetheless, the biomass bistribution of biosphere report suggest more than 1550-fold larger microbial biomass involving bacteria, fungi, archaea, protists and viruses is exist in comparision to all global human population in the biosphere. The rich microbiota act a first line of defence to invade pathogens and affect us both through the environment and microbiome. Unfortunately, a role of pathogen-transmission factors viz. implicit factors (competitive microflora) is still under represented. This study is an attempt from a gold standard correlation methodology using a large pesticide use global data. The non-specific pesticides kill both pests as well as protective microbiota, resulting a loss in rich biodiversity and allow easy pathogen entry to human. Entire predictions were found consistent with the recently observed evidences. These insights enhanced scientific ability to interrogate viral epidemiology and recommended to limit pesticide use for future pandemic prevention.

Co-Ordination of Mucosal B Cell and CD8 T Cell Memory by Tissue-Resident CD4 Helper T Cells

Adaptive cellular immunity plays a major role in clearing microbial invasion of mucosal tissues in mammals. Following the clearance of primary pathogens, memory lymphocytes are established both systemically and locally at pathogen entry sites. Recently, resident memory CD8 T and B cells (TRM and BRM respectively), which are parked mainly in non-lymphoid mucosal tissues, were characterized and demonstrated to be essential for protection against secondary microbial invasion. Here we reviewed the current understanding of the cellular and molecular cues regulating CD8 TRM and BRM development, maintenance and function. We focused particularly on elucidating the role of a novel tissue-resident helper T (TRH) cell population in assisting TRM and BRM responses in the respiratory mucosa following viral infection. Finally, we argue that the promotion of TRH responses by future mucosal vaccines would be key to the development of successful universal influenza or coronavirus vaccines, providing long-lasting immunity against a broad spectrum of viral strains.

Single-Cell Transcriptomics Reveals Core Regulatory Programs that Determine the Heterogeneity of Circulating and Tissue-Resident Memory CD8+ T Cells

During acute infections, CD8+ T cells form various memory subpopulations to provide long-lasting protection against reinfection. T central memory (TCM), T effector memory (TEM), and long-lived effector (LLE) cells are circulating memory populations with distinct plasticity, migration patterns, and effector functions. Tissue-resident memory (TRM) cells permanently reside in the frontline sites of pathogen entry and provide tissue-specific protection upon reinfection. Here, using single-cell RNA-sequencing (scRNA-seq) and bulk RNA-seq, we examined the different and shared transcriptomes and regulators of TRM cells with other circulating memory populations. Furthermore, we identified heterogeneity within the TRM pool from small intestine and novel transcriptional regulators that may control the phenotypic and functional heterogeneity of TRM cells during acute infection. Our findings provide a resource for future studies to identify novel pathways for enhancing vaccination and immunotherapeutic approaches.