Hookworms could offer protection from severe COVID

Prior infection by a parasitic hookworm has been shown to protect mice from severe SARS-CoV-2 disease, offering a potential explanation as to why certain human populations seemed to fare better during the height of the COVID-19 pandemic. That’s according to a new study from the US National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

“This work stemmed from an observation that certain regions in the world didn’t fare as badly from the early days of the pandemic as you would expect,” said NIAID’s Dr Kerry Hilligan.

“Countries throughout Africa and Asia were reporting fewer cases of severe infections, such as hospitalisations or death — much less than the rest of the world. This was the case even when accounting for some confounding factors in the data and lower reporting rates.

“What’s interesting is that these regions strongly correlate or overlap with areas where hookworm infections are endemic — consistently present within the population. We think that perhaps this endemic infection by hookworms is causing a population-wide ‘interference’ in the establishment of more severe SARS-CoV-2 viral infections.”

The idea that parasitic worms — specifically helminths — shape the immune response to subsequent infections by other pathogens is not itself new. Prior research has shown that helminth infection induces responses from both the first-acting part of the immune system (the innate response) and the adaptive arm, which comes into play later. Indeed, mouse studies have shown that prior helminth infection allows the mice to withstand a challenge with influenza virus, which, like SARS-CoV-2, is a respiratory virus.

“What my collaborators Dr Oyebola Oyesola, Dr P’ng Loke and Dr Alan Sher at the National Institutes of Health and I wanted to know is whether we could test this effect in relation to the current pandemic and whether we’d see similar protective effects,” Hilligan said.

The researchers experimentally investigated an observation from a small hospital-based study in Ethiopia in which COVID-19 patients who were co-infected with helminths had a lessened risk of developing severe disease. They then developed a mouse model of SARS-CoV-2, adapted by Hilligan in Sher’s lab.

Animals were infected with a helminth worm, N. brasiliensis, which is a stand-in for human hookworm infection. N. brasiliensis larvae travel to the lung, where they cause damage that is rapidly repaired once the infection clears. When later exposed to lethal doses of SARS-CoV-2, 60% of mice with prior worm infection survived, compared to 20% of mice without N. brasiliensis infection. Further experiments showed that a parasitic worm that is restricted to the gut did not confer the same benefit, suggesting that the lung-migrating aspect of N. brasiliensis played a critical role in boosting resistance to severe SARS-CoV-2 disease.

Next, the scientists sought to distinguish contributions of innate and adaptive components at different points in the course of infection by measuring total viral load in the lung at three and seven days after SARS-CoV-2 exposure. At three days after exposure, viral loads differed only slightly between control animals and those that had been previously infected with N. brasiliensis. However, by the seventh day, worm-experienced mice had much lower levels of SARS-CoV-2 virus in their lungs. This finding indicated that improved adaptive responses, rather than any difference in innate immune actions to thwart virus entry, gave the worm-exposed animals their edge.

The team further defined the specific immune cells involved in the enhanced ability of worm-experienced mice to rapidly control SARS-CoV-2. In N. brasiliensis-exposed mice, the amount of an adaptive immune cell called a CD8 T cell, which can recognise and destroy infected cells, was much higher at seven days after infection than CD8 levels in mice without worm exposure. The importance of this specific type of T cell was confirmed when the investigators treated mice with a substance that depleted CD8 T cells; this led to a large increase in SARS-CoV-2 burden in the worm-experienced mice.

Turning their attention to the immune response step prior to CD8 T cell arrival, the scientists examined whether signals produced by key members of the innate system, called macrophages, differed depending on whether mice had prior worm exposure. In the lungs of worm-exposed mice, the team detected significantly more of macrophage-produced signals known to draw CD8 T cells than were seen in control mice.

“The results show that N. brasiliensis in the lung primes macrophages there so that they can react quickly to recruit CD8 T cells and thus more rapidly control a later SARS-CoV-2 infection,” Oyesola said.

“What’s more, this effect seems to be long-lasting, with the macrophages retaining this very strong ability to recruit and activate CD8 T cells long after the hookworm has been cleared from the body,” Hilligan added.

It is not known whether these results, published in the journal Science Immunology, can explain the observations from epidemiological studies such as the one in Ethiopia — according to Oyesola, that will require follow-up immunologic studies using clinical samples. Oyesola now plans to continue her research at NIAID into how parasitic worm infections remodel innate immune responses and influence subsequent responses to viral infection.

“Looking forward, we want to understand the signals that bring in these T cells to the lung,” Hilligan said. “Leading on from that, we want to understand more about what the worm is doing to create these specialised macrophages, and whether we can replicate this effect without the need for the worm as an intermediary.”

Image credit: iStock.com/Dr_Microbe