How can symptoms of COVID-19 persist after the virus is gone? The answer may lie in the type of immune response triggered by SARS-CoV-2, which resembles one more familiar to those studying the immune response to worm to protozoan parasites. I mentioned this in earlier posts citing observations of clinical characteristics of COVID and how they resembled the response to a parasite rather than a virus. Parasite immunology more closely resembles tumor immunology than that of responses to many viruses and bacteria. This cross reactivity between tumor immunology and the immune response to SARS-CoV-2 has been dramatically illustrated in a recent case of a rare remission of advance Hodgkin lymphoma in conjunction with COVID (https://onlinelibrary.wiley.com/doi/10.1111/bjh.17116). The host must mount a different kind of response to parasites because of their many strategies to evade the immune system, the innate and adaptive components. Therefore, animals and humans have developed a different series of cellular and humoral components unique to parasites, but often with potentially severe collateral damage to normal tissues and organs. There is a delicate balance between controlling a parasite infestation so that it does not consume the host and so completely destroying the parasites that the host “burns down the house to get rid of the rats”, auto destruction of the host in the process of eliminating the parasite and confusion between parasite antigen and self antigens (autoimmunity) https://downloads.hindawi.com/journals/iji/2014/651503.pdf. The remaining “memory” of this response, after the virus is gone, is continuously reactivated by a broad range of stimuli https://jlb.onlinelibrary.wiley.com/doi/epdf/10.1189/jlb.0313113. This primitive process, discussed in my book Type B Cytochromes: Sensors and Switches and cited in previous posts, is built on anticipatory responding to potential pathogens, toxins and physical insults before those insults are actually known or specifically identified. This is good for evolutionary survival but can lead to unnecessary overt nonspecific responses and collateral damage. What is the evidence for such a hypothesis in regards to COVID-19 and how might it lead to treatments, especially for long haulers? As stated in a previous post, the immune response of hospitalized COVID-19 patients falls across a spectrum of immune responses in 3 categories: (1) antiviral (some macrophages and dendritic cells, natural killer cells, cytotoxic T cells, helper and suppressor T cells, antibody making B cells and plasma cells, and gamma interferon; other interferons made by tissue cells: alpha and beta); (2) anti-parasitic granulocyte white blood cells (some special B cells that make IgE, eosinophils, basophils (in tissue mast cells), and all kinds of biochemical mediators: histamine, Prostaglandins, leukotrienes, and kinins); and (3) anti-bacterial and fungal (granulocyte: neutrophils, and monocytes and macrophages). COVID-19 can move through all three types. The worst and most likely cause of the long hauler syndrome is type 2 which was meant for worms and other multicellular localized parasites and can be locally severe and if generalized, fatal. The serum concentrations of IL-17A (a protein that recruits monocytes and neutrophils to an inflammatory site produced by Th17 lymphocytes) and IFN-γ, but not TNF-α or IL-6 (the pro-inflammatory culprits), decrease with age of patients (this might argue against Th17 memory cells being the source of long haulers); therefore, gamma interferon’s ability to prevent viral replication but not induce oxidative damage to host cells, as with TNF-α, is more important in children’s responses. However, as stated in a previous post, evidence supports decline in soluble IL17A receptors, which block TNF-alpha and interferon gamma production by competing with the cellular T17 cellular receptors, leads to more severe COVID19 (supporting Th17 cell involvement). Adults show a more robust T cell response to the viral spike protein compared to pediatric patients shown by increased expression of CD25+ on CD4+ T cells and the frequency of IFN-γ+CD4+ T cells. Also, serum neutralizing antibody titers and antibody-dependent cellular phagocytosis are higher in adults than in pediatric COVID-19 patients. The neutralizing antibody titer increases with age while the IL-17A and IFN-γ serum concentrations decrease. Children seem to be resistant to the severe effects, except in some instances when they display multiple organ inflammation, Kawasaki-like syndrome, because they produce a lot of the anti-inflammatory cytokine IL10. The responses of neonates compared to adults change from increased IL-10 as neonates to balanced IL-10/T helper type 1 (Th1)/Th2/Th17 cytokine levels early in life. This allows protection from pathogens but reduces the chances of severe inflammatory reaction. Th17 cells are the most probable mediators in many human autoimmune and chronic inflammatory disorders, including psoriasis, Crohnˈs disease, rheumatoid arthritis, Multiple Sclerosis, and uveitis https://www.frontiersin.org/articles/10.3389/fimmu.2018.01112/full. The development of pathogenic Th17 cells relies on signals from multiple cytokines: IL‐1, IL‐23, and IL‐6. TGF‐β (transforming growth factor) can promote Th17 development and induces a Th17 response which promotes intestinal muscle hypercontractility that drives worm expulsion. TGFβ-activation by dendritic cells yields this Th17 induction and intestinal contractility and facilitates the expulsion of the parasite Trichinella spiralis in mice. This unique immune response to intestinal helminth expulsion beyond that of classical Th2 driven immunity, highlights the importance of IL-17 in parasitic disease. Th17 protection against parasites is very broad spectrum extending to Th17 cells’ providing robust protection against Trypanosoma cruzi, the intracellular protozoan parasite that causes Chagas disease. Parasites that establish long term chronic infections suppress Th17 immunity by modulation of antigen-specific CD4+ T responses. This is seen in human infection with the worm parasite Strongyloides stercoralis https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546867/pdf/nihms-704134.pdf. Th17 cells of infected people showed significantly decreased responses upon antigen-stimulation, but following treatment, significantly increased the antigen-specific responses of Th17 cells. Th17 cells produce pro-inflammatory cytokines, including IL-17A, IL-17F, and IL-22. This cytokine production not only promotes accumulation of immune cells, such as macrophages, neutrophils and lymphocytes, at inflammatory sites, but also can cause collateral tissue damage. Other Th17 cells can negatively regulate immune responses by secreting immunosuppressive factors, such as IL-10 as noted in the response of children to COVID. Th17 cells are required for vaccine-induced protection from pulmonary infection with the pathogenic fungi Coccidioides posadasii, Histoplasma capsulatum, and Blastomyces dermatitidis, fungal pathogens causing systemic mycoses in humans. IL-17 is required for neutrophil and macrophage recruitment to the lungs. This balance is evidently what helps dispose of or suppress parasites and perhaps SARS-CoV-2 virus, or, if out of balance, severe acute or chronic persistent long hauler pathologies https://www.thermofisher.com/us/en/home/life-science/cell-analysis/cell-analysis-learning-center/immunology-at-work/t-helper-17-cell-overview.html. Some in vitro experiments suggest a benefit from Vitamin D because of its effects on Th17 cells. These cells are characterized by the chemokine receptor CCR6, RORC expression, and production of IL-17A, IFNγ, and TNFα. Using rheumatoid arthritis (RA) as a model of autoimmune disease, investigators demonstrated that pro-inflammatory memory CCR6+ Th cells can switch into anti-inflammatory cells by treating them with the active vitamin D metabolite 1,25(OH)2D3. Memory CCR6+ Th cells were sorted from healthy controls or treatment-naïve patients with early rheumatoid arthritis (RA) and cultured with or without 1,25(OH)2D3. Vitamin D3 inhibited pro-inflammatory cytokine production, IL-17A, IL-17F, IL-22 and IFNγ, in memory CCR6+ Th cells from both healthy controls and RA patients. This inhibition was accompanied by induction of anti-inflammatory factors, IL-10 and CTLA4 https://www.frontiersin.org/articles/10.3389/fimmu.2019.01504/full. Perhaps, this approach provides a means to test the hypothesis that Th17 memory cells are the root cause of long haulers. Also, antioxidants may help because the pro-inflammatory cytokines enhance the production of reactive oxygen species which are mediators of the anti-parasitic effector mechanism and collateral pathology. These benefits remain to be seen.
The anti-parasitic immune response leading to long haul and neurological disease has gained further support in a new paper showing the involvement of the cytokine CCL11, eosinophil chemotactic protein and eotaxin-1 (https://www.biorxiv.org/content/10.1101/2022.01.07.475453v1.full.pdf).
Global Biosurveillance 