key: cord-0910092-hc9kezcu authors: Siles-Lucas, Mar; González-Miguel, Javier; Geller, Ron; Sanjuan, Rafael; Pérez-Arévalo, José; Martínez-Moreno, Álvaro title: Potential influence of helminth molecules on COVID-19 pathology date: 2020-10-15 journal: Trends Parasitol DOI: 10.1016/j.pt.2020.10.002 sha: d3a91f5fb6abc78be295a6cb7c28ef81320d9528 doc_id: 910092 cord_uid: hc9kezcu The parasitology research community has been fostered in recent months to investigate the influence of parasite co-infection on COVID-19 outcomes. Following this call, we share here our approach to analyze the effect of the trematode Fasciola hepatica as a modulator of SARS-CoV-2 infection and of COVID-19 pathology. Helminth parasites have adapted to their hosts during long co-evolution processes, which usually result in chronic disease with low mortality and variable morbidity. During this evolutionary co-adaptation with their hosts, including vertebrate hosts, parasites have contributed to the modulation of several molecular and physiological host mechanisms, e.g. the immune system. Thereby, helminth parasites trigger a modulated Th2 response in their vertebrate hosts, resulting in an immune reaction with a tightly controlled inflammatory component, including the inhibition of pro-inflammatory cytokines and the induction of a hyporesponsive state involving IL-10-producing T regulatory (Treg) cell populations [1] . In addition, the hygiene hypothesis proposes that the absence of helminth infections in the population of developed countries, thus the lack of immunological stimuli of helminth parasites during childhood, has propitiated the rise of autoimmune diseases with an exacerbated inflammatory component (e.g., allergy, asthma and rheumatoid arthritis, among others) [2]. We have read with interest the comment by Bradbury et al. [3] , in which the authors discuss the potential role of helminth co-infections in the modulation of hyperinflammatory responses against SARS-CoV-2. Severe cases of COVID-19 show an exacerbated immune response affecting lungs. The innate immune response to tissue damage caused by the virus could result in an acute respiratory distress syndrome, characterized by the rapid onset of generalized inflammation in lungs and subsequent death by respiratory distress [4] . This is due to a "cytokine storm", in which proinflammatory cytokines, e.g. IL6, dominate [5] . One of the compounds showing efficacy against this hyperinflammation in COVID-19 is Tocilizumab, a monoclonal antibody targeting the IL6 receptor usually administered to patients with auto-immune rheumatoid arthritis. This causes general immunosuppression and thus could be of The use of specific helminth derivatives as therapeutic tools of auto-immune diseases has been proposed. Specifically, the helminth parasite Fasciola hepatica has shown immunomodulatory properties, and several molecules from this parasite have been described as potent immunomodulators [7] . Derivatives of these molecules in their synthetic, safe formats have given rise to promising results, e.g., a 68 mer peptide of HDM has shown to inhibit inflammation and airway hyperreactivity in murine experimental asthma [8] and the fatty acid binding recombinant protein Fh15 blocked the lipopolysaccharide induced cytokine storm in a murine model [9] . As a result, recombinant safe-to-use forms of the above-mentioned molecules are available. Devoid of our chronic helminthic infections, humans could be more susceptible to not only develop hyperinflammatory pathology related to different stimuli, including viruses, but also be more susceptible to infection by emerging viruses. Helminth schistosome infection has been used as a protective anti-inflammatory strategy against viruses such flu A or murine pneumonia virus by Sheer et al. [10] . Additionally, these authors also showed that mice with schistosomiasis were significantly protected against respiratory viral infections [10] . On the other hand, mice infected with the nematodes Regulation of the host immune system by helminth parasites Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study IL-6 may be a good biomarker for earlier detection of COVID COVID-19 and treatment with NSAIDs and corticosteroids: should we be limiting their use in the clinical setting Helminth defence molecules-immunomodulators designed by parasites! Front The parasitic 68-mer peptide FhHDM-1 inhibits mixed granulocytic inflammation and airway hyperreactivity in experimental asthma Fh15 blocks the lipopolysaccharide-induced S. mansoni bolsters anti-viral immunity in the murine respiratory tract Immunology. How helminths go viral Helminth modulation of lung inflammation The authors want to thank financial support from Ministry MINECO, Spain (Project The authors declare no competing interests. i https://hgis.uw.edu/virus/ ii https://pti-saludglobal-covid19.corp.csic.es/