#SARS-CoV-2 Tests the #Hygiene Hypothesis

The #hygiene hypothesis was first proposed by #David Strachan, a London epidemiologist, in 1989. After studying over 17,000 British children he concluded that babies who had siblings were less prone to development of eczema, hay fever or allergic rhinitis. In 2000 he named this theory the “hygiene hypothesis”. Since these earlier iterations the hygiene hypothesis has been expanded to include inflammatory diseases, autoimmune diseases and metabolic syndrome.

At the core of the hygiene hypothesis is the belief that certain microorganisms that have co-evolved with humans, in particular the gut flora and #helminths (worms), have beneficial #immunomodulatory effects. And the cornerstone of these effects, in turn, is the ability to elicit an anti-inflammatory T helper 2 (Th2) cell immune response and counter the often-detrimental proinflammatory effects mediated by a Th1 immune response. Since helminths and humans are known to have largely lived in harmony throughout the ages, this article now takes a closer look at how this is achieved.

The most prevalent of these parasites are the #soil-transmitted helminths (STHs), estimated to infect around 1.5 billion people worldwide. These include Ascaris lumbricoides, Trichuris trichiura, and the hookworms Ancylostoma duodenale and Necator americanus. STHs have been demonstrated to be masters of immunoregulation thanks to their ability to escape host defence and establish chronic infections. Molecular crosstalk between the host and the parasite starts immediately after their first encounter and this determines the development course of both the innate and adaptive arms of the immune response. As mentioned, helminths induce a Th2 type response driven by cytokines, such as interleukin-3 (IL-3), IL-4, IL-5, IL-9, IL-10, and IL-13.

These cytokines impact the innate immune response by increasing the levels of circulating IgE antibodies, eosinophils, basophils, and mast cells. They also influence the chief standard bearer of that response, the macrophage, triggering what is known as alternatively activated macrophages (AAMs). The anti-inflammatory role of AAMs in obesity and autoimmune diseases is well documented. As regards the adaptive immune response, interactions between helminth-derived molecules, e.g. lipids, proteins, glycoconjugates present either on the parasite surface or in the excretory-secretory (ES) products, and host cells modify dendritic cells that present helminth antigens to the T cells. This results in downregulation of the adaptive response by triggering regulatory T cells (Tregs) and B cells (Bregs). And so the stage is set for harmonious helminth-host coexistence. With its anti-inflammatory effects, the helminth suppresses the host immune response, protecting the latter against any tissue damage caused by the worm itself as well as against unrelated immunopathology resulting from excessive proinflammatory responses as seen in autoimmune diseases, obesity and allergic diseases.

Data supporting these beneficial effects of helminths have been widely reported in the medical literature since the formulation of the hygiene hypothesis. The emergence of SARS-CoV-2 in late 2019 could perhaps make a decisive contribution to corroboration or rebuttal of this hypothesis. This is because the hallmark of #Covid-19 disease severity, caused by #SARS-CoV-2, is the widely reported cytokine storm driven by proinflammatory cytokines, such as IFN-g, IL17, IL-23, and TNF-a. While individuals infected with helminths before contracting SARS-CoV-2 exhibit a predominantly anti-inflammatory innate and adaptive immune response, as described above, the co-infected host (now harbouring SARS-CoV-2 in addition to the helminth) needs a strong Th1 type lung microenvironment in the initial stages to control SARS-CoV-2 infection. How this plays out overall is the subject of intense research.

There is emerging evidence that the elevated Th2 induced cytokines and tissue reparative growth factors reduce lung inflammation and damage and also decrease expression of the ACE2 receptors used by SARS-CoV-2 as the gateway to entering the human host. It has also been found that helminth-induced IL-4 signalling in cytotoxic T cells (CD8+), which form the classic arm of the adaptive cell-mediated immunity needed to control viruses, expands bystander or virtual memory CD8+ T cells for early control of viral infection. Another key player triggered by helminth infection is the eosinophil, which could prove highly relevant in Covid-19 disease. This is due to the fact that SARS-CoV-2, unlike its predecessor SARS-CoV-1, appears to be adept at suppressing the first lines of defence against viruses thanks to the fact that its genome contains several open reading frames (ORF) that appear to be targeted against host anti-viral defence strategies. This includes inhibiting response to interferon and decreasing the expression of MHC I receptors needed to present viral antigens to the CD8+ cytotoxic T cells.

A look at #WHO Situation Report 152 of 20 June 2020 shows that the number of Covid-19 infections for Africa was 208 535 cases with 4 750 deaths vs 2 509 750 cases with 192 645 deaths for Europe. This demonstrates a mortality rate of 2.27% for Africa vs 7.67% for Europe. That trend is reflected when looking at these data on the basis of a high- vs low-income country. Researchers who compared the course of SARS-CoV-2 infection in persons infected with vs not infected with helminths found that the severity of Covid-19 disease was inversely related to coinfection with STHs. For example, in a study conducted in Ethiopia, 751 Covid-19 patients were screened for intestinal parasites between July 2020 and March 2021. Of these 284 (37.8%) had intestinal parasitic infection. Only 27/255 (10.6%) severe COVID-19 patients were co-infected with intestinal parasites, while 257/496 (51.8%) non-severe COVID-19 patients were parasite positive (p<0.0001). There were 11 deaths (1.5%), and all were among patients without parasites (p = 0.009).

Further studies with larger sample sizes are urgently needed to ascertain whether the significantly lower Covid-19 mortality rates across helminth belt countries could possibly be attributed to helminth-mediated immunomodulatory effects. This is all the more important because among the neglected tropical diseases in the #WHO Roadmap 2021-2030 “targeted for elimination as a public health problem” by 2030 are STHs and Schistosoma. SARS-CoV-2 could perhaps offer a unique opportunity to shed new light on Strachan’s hygiene hypothesis.