Beyond the acute illness: Exploring long COVID and its impact on multiple organ systems.

Unprecedented worldwide health catastrophe due to the COVID-19 pandemic has ended up resulting in high morbidity and mortality rates. Even though many people recover from acute infection, there is rising concern regarding post-COVID-19 conditions (PCCs), often referred to as post-acute sequelae of SARS-CoV-2 infection (PASC) or "long COVID." The respiratory, cardiovascular, neurological, and endocrine systems are just a few of the many organ systems that can be impacted by this multifarious, complicated illness. The clinical manifestations of long COVID can vary among individuals and may include fatigue, dyspnea, chest pain, cognitive impairment, and new-onset diabetes, among others. Although the underlying processes of long COVID are not fully understood, they probably involve unregulated immune response, persistent generation of pro-inflammatory cytokines (chronic inflammation), autoimmune-like reactions, persistent viral replication, and micro-clot formation. To create successful treatments and care plans, it is essential to comprehend the immunological mechanisms causing these difficulties. The pathogenesis of long COVID should be clarified and potential biomarkers to help with diagnosis and treatment should be sought after. To reduce the burden of long COVID on people and healthcare systems around the world, the need for long-term monitoring and management of long COVID problems should be emphasized. It also underscores the significance of a multidisciplinary approach to patient care. The goal of this review is to carefully evaluate the clinical signs and symptoms of long COVID, their underlying causes, and any potential immunological implications.

Tumor-associated macrophages: an effective player of the tumor microenvironment.

Cancer progression is primarily caused by interactions between transformed cells and the components of the tumor microenvironment (TME). TAMs (tumor-associated macrophages) make up the majority of the invading immune components, which are further categorized as anti-tumor M1 and pro-tumor M2 subtypes. While M1 is known to have anti-cancer properties, M2 is recognized to extend a protective role to the tumor. As a result, the tumor manipulates the TME in such a way that it induces macrophage infiltration and M1 to M2 switching bias to secure its survival. This M2-TAM bias in the TME promotes cancer cell proliferation, neoangiogenesis, lymphangiogenesis, epithelial-to-mesenchymal transition, matrix remodeling for metastatic support, and TME manipulation to an immunosuppressive state. TAMs additionally promote the emergence of cancer stem cells (CSCs), which are known for their ability to originate, metastasize, and relapse into tumors. CSCs also help M2-TAM by revealing immune escape and survival strategies during the initiation and relapse phases. This review describes the reasons for immunotherapy failure and, thereby, devises better strategies to impair the tumor-TAM crosstalk. This study will shed light on the understudied TAM-mediated tumor progression and address the much-needed holistic approach to anti-cancer therapy, which encompasses targeting cancer cells, CSCs, and TAMs all at the same time.

FOXP3/HAT1 Axis Controls Treg Infiltration in the Tumor Microenvironment by Inducing CCR4 Expression in Breast Cancer.

Infiltrating T-regulatory cells in the tumor microenvironment is a key impediment to immunotherapy and is linked to a poor prognosis. We found that tumor-infiltrating Tregs express a higher expression of the chemokine receptor CCR4 than peripheral Tregs in breast cancer patients. CCL22 and CCL17 are released by tumor cells and tumor-associated macrophages, attracting CCR4+ Tregs to the tumor site. The Treg lineage-specific transcription factor FOXP3 changes the CCR4 promoter epigenetically in conjunction with HAT1 to provide a space for FOXP3 binding and activation of the CCR4 gene. To increase CCR4 expression in Tregs, the FOXP3/HAT1 axis is required for permissive (K23 and K27) or repressive (K14 and K18) acetylation of histone-3. In murine breast and melanoma tumor models, genetic ablation of FOXP3 reduced CCR4+ Treg infiltration and tumor size while also restoring anti-tumor immunity. Overexpression of FOXP3, on the other hand, increased CCR4+ Treg infiltration, resulting in a decreased anti-tumor immune response and tumor progression. These findings point to FOXP3 playing a new role in the tumor microenvironment as a transcriptional activator of CCR4 and a regulator of Treg infiltration.

Transcriptional regulation of VEGFA expression in T-regulatory cells from breast cancer patients.

The initiation of new blood vessel formation (neo-angiogenesis) is one of the primary requirements for the establishment of tumor. As the tumor grows beyond a certain size, a hypoxic-condition arises in the inner core of tumor, triggering the release of chemokines, which attract T-regulatory (Treg) cells in the tumor-site. The presence of FOXP3, a lineage-specific transcription factor, expressing Treg cells in various types of tumor implements immunosuppressive and tumor-promoting strategies. One such strategy is the invitation of endothelial cells for neo-vascularization in the tumor site. Here we report that as the disease progresses, Treg cells from breast cancer patients are capable of secreting high-amount of VEGFA. The VEGFA promoter lacks Treg-specific transcription factor FOXP3 binding site. FOXP3 in association with locus-specific transcription factor STAT3 binds to VEGFA promoter to induce its transcription in Treg cells obtained from breast cancer patients. Treg cell-secreted VEGFA induces neo-angiogenesis from endothelial cells under in-vitro conditions. Targeting Tregs in mice with breast tumor reduces tumor growth as well as the level of neo-angiogenesis in the tumor tissue.

Tumor-infiltrating T-regulatory cells adapt to altered metabolism to promote tumor-immune escape.

Tumor mass and its microenvironment alter host immune system in various ways to promote tumor growth. One of the modifications is evasion of immune surveillance by augmenting the number of Tregs in tumor vicinity. Elevated levels of Tregs are seen in peripheral circulation and tumor tissue of cancer patients. Cancer cells release several chemokines to attract Tregs in tumor-site. Infiltration of Tregs has clinical significance because being immunosuppressive infiltrating Tregs suppress other immune cells making the tumor microenvironment favorable for tumor growth. On the other hand, infiltrating Tregs show metabolic alteration in tumor microenvironment which allows their selective survival over the others. Persistence of Tregs in the tumor microenvironment and subsequent immunosuppression makes Tregs a potential therapeutic obstacle and the reason behind the failure of immunotherapy. In this review, we emphasize the recent development in the metabolic adaptation of tumor-infiltrating Tregs and the therapeutic approaches to boost immunity against cancer.

Assessment of Hymenoptera and Non-Hymenoptera Insect Bite and Sting Allergy Among Patients of Tropical Region of West Bengal, India.

West Bengal, India, is inhabited by abundance and variety of insects that triggers sensitization in some humans to inhalant allergens and/or insect stings/venoms. Lack of research on this topic prevented accurate diagnosis and proper follow-up treatments to patients suffering from insect-induced allergies. The aim of our study was to identify the allergy-causing insects and evaluate resulting sensitization among a study population in West Bengal, India. The skin prick test (SPT) evaluated sensitivity of 450 patients who sought treatment at the Allergy and Asthma Research Center from July 2017 to June 2018. Eight insect allergens were tested: Common Black Ant (Lasius niger, Linnaeus 1758), Fire Ant (Solenopsis invicta, Buren 1972), Honey Bee (Apis cerana indica, Fabricius 1798), Common Wasp (Vespula vulgaris, Linnaeus 1758), Mosquito (Aedes aegypti, Linnaeus in Hasselquist 1762), American Cockroach (Periplaneta americana, Linnaeus 1758), House Fly (Musca domestica, Linnaeus 1758), and Grasshopper (Gesonula punctifrons, Stal 1861). From a total of 450 patients evaluated, 370 patients had positive SPT reaction from at least one of the 8 insect allergens tested. Sensitivity to some Hymenoptera insects (common black ant, 87.62%; fire ant, 84.59%; and honey bee, 67.02%) was found in higher proportion than non-Hymenoptera group (mosquito, 66.67%; American cockroach, 33.33%; house fly, 10.41%; and grasshopper, 5.14%). There was significant difference in sensitivity among child, adolescent, and adult (P < 0.001). While female patients showed more sensitivity than males to SPT, the difference was statistically insignificant. In regards to occupation, farmers and bee keepers were most sensitive of field workers sensitive to Hymenoptera-derived allergens.

Andrographolide binds to ATP-binding pocket of VEGFR2 to impede VEGFA-mediated tumor-angiogenesis.

Vasculogenesis and angiogenesis are process of formation of blood vessels. Blood vessels are evolved to distribute nutrients and oxygen to distant organs. These vessels are crucial for growth and repair of wounded tissue. During tumor condition there occurs imbalance in the growth of blood vessels which leads to neo-angiogenesis. Neo-angiogenesis is major perpetrator behind the establishment of tumor. Tumor cells secrete pro-angiogenic factor VEGFA which binds to VEGFR2 present over surface of endothelial cells and triggers formation of new blood vessels. To inhibit tumor-angiogenesis, a physiologically-safe small molecule inhibitor was screened which can potentially interact with kinase domain of VEGFR2 and inhibit its activity. Molecular-docking module and biochemical analysis identified andrographolide as one of the best docking molecules that binds to ATP-binding pocket of VEGFR2 and inhibits its kinase activity. Thus, for a more radical approach towards safe VEGFR2 inhibitor, andrographolide was repurposed to inhibit tumor-angiogenesis and reduce tumor burden.

Sensitization to Common Aeroallergens in the Atopic Population of West Bengal, India: An Investigation by Skin Prick Test.

BACKGROUND: Aeroallergen sensitization is increasing worldwide. The optimal management of allergic disease requires the identification of the allergic sensitivities of the patient. Complete data of offending aeroallergens are scant from West Bengal, India. Hence, we employed a retrospective analysis of an atopic population of West Bengal to investigate the rate of sensitivity toward common aeroallergens including pollens, molds and house dust mites. OBJECTIVES: The aim of the present study was to evaluate the profile of skin prick test (SPT) reactivity of an atopic population of eastern India. METHODS: The prevalence aeroallergen sensitization was investigated by SPT along with a questionnaire survey of patients who visited the Allergy and Asthma Research Center of West Bengal, India, from June 2016 to May 2018. Patients were categorized according to the demographic (age, gender) and clinical aspects. Statistical tests were applied to differentiate between age and gender of the sufferers. RESULTS: 524 out of 605 patients exhibited a positive SPT response toward one or more aeroallergens tested. One-way ANOVA following Tukey's post hoc test reveals the age group of 15-40 years was more sensitized than that of < 15 years and no male-female discrimination was found using the paired t test. House dust mites, namely Dermatophagoides pteronyssinus and Dermatophagoides farinae, elicited most significant SPT results (80.34 and 84.92%, respectively) followed by Cocos (73.28%) and Azaridacta (57.25%) pollen. The most sensitive mold was Alternaria alternata (26.9%). Allergic rhinitis, bronchial asthma and atopic dermatitis were recorded as the common symptoms. Other influencing factors were family history, nature and season/time of onset and house conditions. CONCLUSION: Following the increasing trend, house dust mite sensitization still held the dominance like in any other Indian population reported earlier. This study would pave the way to construct a standard and minimal SPT panel for the atopic patients of eastern India.

Evaluation of Sensitivity Toward Storage Mites and House Dust Mites Among Nasobronchial Allergic Patients of Kolkata, India.

House dust mites (HDMs) are the major constituents of house dust (HD). HD and HDM sensitization is well documented worldwide. Storage mite (SM) sensitization is presently lacking from India. The present study evaluated the sensitization of both HDM and SM among 372 allergic rhinitis patients reported to the Allergy and Asthma Research Center of Kolkata metropolitan, India. HD samples were collected from the patients' home and analyzed for the major constituent mites. HD and six constituent mites Dermatophagoides pteronyssinus (DP), Dermatophagoides farina Hughes (Acari: Pyroglyphidae) (DF), Blomia tropicalis (BT), Acarus siro Linnaeus (Acari: Acaridae) (AS), Lepidoglyphus destructor (LD), and Tyrophagus putrescentiae (Schrank) (Acari: Acaridae) (TP) are tested for the allergenic potential through Skin Prick Test (SPT). Three SMs, namely AS, LD, and TP, were newly included in the mite SPT extract for the first time in Kolkata. In total, 330 patients showed significant positive SPT toward any one allergen tested. HD was the major elicitor exhibiting 92.42% response. Individuals of age group 15-40 were the worst sufferers. DF showed the highest sensitization (87.87%) among the dust mites. The SMs also contributed significantly to prove their sensitizing potential. SPT rates for AS, LD, and TP were 33, 25, and 18%, respectively. SPT grades and total Immunoglobulin E (IgE) were positively correlated for each of the allergens. Most of the patients were multi-sensitized (95%) and represented markedly high total IgE levels (>500 IU/ml). Three SMs proved to be significant allergens for the studied population. The sensitization toward these SMs is first time reported from India and can be recommended for inclusion of routine SPT for better outcome in the future.