Translational Immunology, Osteoimmunology & Immunoporosis Lab
(TIOIL)
The birth place of "Immunoporosis" : Immunology of Osteoporosis
Dr Rupesh Srivastava conferred with the prestigious “Prof. G. P. Talwar Young Scientist Award” for the year 2019 from Indian Society for the study of Reproduction & Fertility (ISSRF), India in recognition of his outstanding contribution in the field of Reproductive Health (Post-menopausal osteoporosis).
Dr. Rupesh K. Srivastava
Welcome to Osteoimmunology group at AIIMS, New Delhi. During my doctoral research work form NCCS, Pune I got a glimpse of the very exciting and thrilling field of Immunology. This led me to further continue my research work in the field of Bone and Immunology at Columbia University Medical Centre, NY, USA and Roswell Park Cancer Institute (RPCI), New York, USA. After coming back to India in 2013 as an Assistant professor at Central University, Sagar (MP), and now at All India Institute of Medical Sciences (AIIMS), New Delhi, I am actively involved in deciphering this new field which is still in its very naive state. My research specifically focuses on the cellular and molecular interactions between the Immune and Bone systems i.e “Osteoimmunology” (Frontiers in Biosciences, 2018), a very recent branch of modern biology which specifically deals with the interplay between the immune cells (CD4, CD8 T cells, B cells, DCs, Macrophages, ILCs etc.) and bone cells (Osteoclast, Osteoblast & Osteocytes). During normal physiology both systems are at homeostasis but during an imbalance due to various stimuli (infection, autoimmunity, environment, ageing, hormones etc.), it leads to various inflammatory conditions such as Osteoarthritis, Rheumatoid Arthritis & Osteoporosis (viz. post-menopausal osteoporosis). Thus, a molecular understanding of these interactions is at the heart of my research which would ultimately lead to discovery of novel therapeutics for various inflammatory bone conditions.
CURRENT RESEARCH FOCUS
I - Research in “Immunoporosis”
One of the key bone diseases associated with aging and postmenopausal condition is osteoporosis which affects more than 200 million individuals worldwide. Menopause is a major risk factor for osteoporosis. Osteoporosis is termed as a “Silent Killer” because bone loss occurs without symptoms and in many cases, the first "symptom" is a broken bone itself. The worldwide cost burden of osteoporosis (for all ages) is forecasted to increase to USD 131.5 billion by 2050. In fact, fifty percent of the women population over the age of 50 will experience an osteoporosis-related fracture in their lifetime. Also, there is elevated risk of wrist, hip, or spine fracture due to osteoporosis which is estimated to be parallel to the risk of heart disease. In women’s over age of 45, osteoporosis accounts for more days spent in hospital than diabetes, heart and cancer taken together.
Osteoporosis or enhanced bone loss is affected by various environmental factors including sex, diet, age, toxins etc. Our group for the first time clearly highlighted and summarized the specific role of immune system in the development and pathophysiology of post-menopausal osteoporosis leading to establishment of a new field of biology proposed by me as “Immunoporosis: The Immunology of Osteoporosis” with special emphasis on the role of both Innate and Adaptive immune system in pathophysiology of Osteoporosis (Frontiers in Immunology, 2018; PNAS-India, 2021 & J. of Inflammation Research, 2022).
II - Pioneers in establishing the “Role of regulatory B cells (Bregs) in Osteoporosis”
We are pioneers in establishing that regulatory B cells (Bregs) viz. CD19+IL-10+ and CD19+CD1dhiCD5+IL-10+ Bregs exhibit anti-osteoclastogenic potential. Moreover, we for the first time reported that reduction in Bregs number observed in osteoporortic mice model is one of the prime contributing factors towards inflammatory bone loss observed in osteoporosis (Frontiers in Immunology, 2021). These results of ours thus provide novel insight into Bregs biology in the context of osteoporosis. Moreover, apart from these Bregs population, we also observed that other Bregs population with characteristic phenotypes of CD19+FOXP3+ Bregs and CD19+CD11b+ Bregs are also found to be decreased in case of osteoporotic mice model. Thus, further studies are need of the hour to fully dissect and establish the role of various population of Bregs in post-menopausal osteoporotic conditions which would thereby lead towards future employment of Bregs based cellular therapy in ameliorating inflammatory bone loss observed in osteoporosis.
III - Research in “Osteomicrobiology” "Osteometabolism" & “Osteonutrition biology”
Our group is at the forefront in therapeutically managing bone loss in post-menopausal osteoporotic mice model via dietary changes (Osteonutrition-salt and sugar intake, food preservatives) (Scientific Reports, 2018) along with identifying various probiotic strains for enhancing bone health a field called as “Osteomicrobiology” (Bone Reports, 2018; Nutrition, 2018 & Scientific Reports, 2021). My group is involved in dissecting the role of Probiotics on Bone health viz. post-menopausal osteoporosis in ovx mice model. The GM interacts with the host immune system (a two-way communication) thereby providing various beneficial effects on the host. Our group is interested in the novel role of probiotics in regulating bone health through its effect on the host immune system. Thus, the current research opens a new arena of research, called as "Osteo-Microbiology" (Frontiers in Microbiology, 2022), which is a delicate interplay between the host Immune system, Bone system and Gut Microbiota, which if exploited will ultimately lead to various health benefits (eg. enhanced bone mass). Osteo-microbiology thus is a perfect integration of three independent fields of biology and thus future research on the same will be of immense clinical importance and will benefit people by providing a novel treatment option to various inflammatory conditions including post-menopausal osteoporosis. We are pioneer in this field of biology in India and have got novel findings in the field. Exciting initial results (published and unpublished) in our lab had suggested a strong positive interaction between the gut microbiota + Immune system + bone System (= Osteomicrobiology). Our results for the first time demonstrate that administration of specific probiotic strains such as Lactobacillus acidophilus (Bone Reports, 2018); Bacillus clausii (Nutrition, 2018); Lactobacillus rahmnosus (Scientific Reports, 2021) and Bifidobacterium longum (Frontiers in Immunology, 2022) inhibits ovx-induced post-menopausal osteoporosis in mice by modulating host immune system thereby validating the use of probiotics as possible novel therapeutics in treatment of post-menopausal osteoporosis, RA and various other inflammatory diseases.
We are further emphasizing on the role of GUT-associated metabolites (GAMs) such as short-chain fatty acids (SCFAs), medium-chain fatty acids (MCFAs), indole derivates, bile acids, etc., in regulating the energetics of bone cells and their plausible role in maintaining bone health. Emphasis is importantly placed on highlighting knowledge gaps in this novel field of skeletal biology, i.e., “Osteometabolism” (proposed by our group) (Cells, 2022) that need to be further explored to characterize the physiological importance of skeletal cell bioenergetics in the context of human health and bone related metabolic diseases.
IV - Research in “Osteo-toxicology”
We are pioneer in dissecting the effect of various environmental pollutants (Cyanotoxins, Particulate Matter-PM etc.) on the Osteoimmune system with immense future implications in the field, a point of major concern with increase in worldwide pollution on all fronts. Cyanobacteria (CB) represent group of photoautotrophic bacteria’s occurring in fresh as well in brackish water bodies. Chronic or repeated exposure to low cyanotoxin levels is one of most important factors affecting human health in general. Different cyanobacteria toxins have been implicated with serious health issues worldwide due to the production of various bioactive and toxic metabolites especially microcystins (MCs). According to World Health Organization (WHO) 1𝜇g/L of MC-LR is admissible, but the concentration of microcystins in present day water bodies is many times beyond the recommended guidelines. We for the first time have demonstrated the direct effect of MC-LR on bone health via affecting the host osteo-immune system (Environmental Pollution, 2018). Our study thus highlights the risk associated with intake of contaminated water and food not only to our immune system but also to our bones establishing a direct link between MC-LR intake and enhanced bone loss. Our study for the first time have established a direct link between the intake of cyanotoxin viz. MC-LR (a WHO categorized carcinogen, present in all water bodies) and enhanced bone loss thereby giving a strong impetus to the naïve field of “Osteo-toxicology”, a termed coined by my group.
V - Research in “Osteofertility”
India faces an acute burden of rising infertility with 27.5 million couples actively seeking children, suffer from infertility. While female factor accounts for 40-50% of cases, male factor is also on the rise, with 30-40% of cases. In the last five years alone there has been a 20-30% rise of infertility cases in India. Determining the root cause of infertility is a complex process involving interplay between genetic, hormonal and environmental factors including diet. According to Indian Society of Assisted Reproduction, infertility affects one in every six couples. Recent advances have dramatically increased our understanding of how organ system works through different physiologies to regulate a function. Bone-health is already reported to be linked with male-reproductive health, also recent study from our lab (Scientific Reports, 2018), had established the role of high dietary salt (HSD) intake in regulating bone-health via its effect on host osteo-immune system. Therefore, we are next asking the question: what is the link between dietary-salt-intake and male fertility? Leading to birth of a novel scientific discipline coined by our group as “Osteofertility”. Also, no study till date had ever-linked the negative effects of dietary-salt-intake on male fertility. We thus are actively involved in dissecting the role of dietary-salt-intake on male-fertility via modulation of complex interplay between host “Immune-Bone-Testis” axis. Having proven the undesired effect of dietary-salt on male fertility, it will be of immense clinical importance for those affected with infertility as dietary factors have proven combinatorial role in manifesting fertility related problems. We already have interesting unpublished data about the negative effects of HSD on male fertility. Establishing a direct link between dietary-salt-intake and male fertility will be of immense clinical importance for managing fertility disorders in males. Thus, dietary cut down of salt intake may play an important role in managing fertility. Moreover, the present study would associate that dietary salt not only effects bone loss but at the same time also modulates fertility in males. The results of this study will establish dietary modulation of salt intake as a viable treatment/management option in male reproductive health thereby combating the increasing fertility problems of the country. The present study would pave a path towards a better understanding of the intricate relationship between diet and Osteofertility.
VI - Research in “Phyto-Therapeutics” & Bone Health”
Till date, various drugs have been proposed for the treatment of osteoporosis and other bone related implications with variable results. Extensive safety concerns are of utmost importance with treatment, as presently accessible drugs (strontium, bisphosphonates and estrogen-replacement-therapy) in treating osteopo-rosis are associated with several undesirable effects. The latest research in the area of photomedicine had sparked interest in harnessing the active components from plants in both disease control and management across the globe. My group is involved in comprehensively identifying novel plants and their phytoconstituents with potent osteoprotective properties. We further are actively engaged into identifying and developing various novel Phyto-therapeutics for treatment and management of Osteoporosis. We have identified 40 such plants with osteoprotective properties (Frontiers in Bioscience, 2020). We have already published and established the anti-osteoporotic properties of Cissus quadrangularis (Hadjod, Cells, 2023), Moringa oleifera (Drumstick) and Crocus sativus (Saffron, Phytomedicine Plus, 2022) in mice. Thus, a molecular insight into this novel field of biology would thus leads to development of innovative approaches for the prevention and treatment of post-menopausal osteoporosis and other bone pathologies.
VII - Research in “Immunology of COVID-19 & ARDS induced Bone Health"
SARS-CoV-2 infection causes excessive production of pro-inflammatory cytokines thereby leading to the development of “Cytokine Storm Syndrome.” This condition results in uncontrollable inflammation that further imposes multiple organ-failure eventually leading to death. SARS-CoV-2 induces unrestrained innate immune response and impairs adaptive immune responses thereby causing tissue damage. Thus, understanding the foremost features and evolution of innate and adaptive immunity to SARS-CoV-2 is crucial in anticipating COVID-19 outcomes and in developing effective strategies to control the viral spread. Recently we are also exploring the Immunology of COVID-19 with emphasis on managing Cytokine Storm induced by COVID-19 via both Biotics and Phytotherapeutic interventions (International Reviews of Immunology, 2021 & Frontiers in Bioscience, 2021). We are further looking into the implications of long COVID and Bone Health (Inflammation Research, 2022).
COLLABORATIONS
