Prior Common Cold: A Protective Factor Against Covid-19?
By: Shin Jie Yong
Tags: Technology, Innovation, Health, Covid 19, Science

Prior Common Cold: A Protective Factor Against Covid-19?

When T-cells learn from other coronaviruses and outsmart the novel SARS-CoV-2 — cross-immunity.

One reason why Covid-19 is so lethal is some is that the immune system has never encountered it before. So, the immune system mounts all sorts of reactions, some of which might be unsafe.

A July study in Nature, titled “Longitudinal analyses reveal immunological misfiring in severe COVID-19,” showed that the immune system of Covid-19 patients mounted anti-fungal and anti-parasitic reactions. It seems like the immune system is doing trial-and-error against the novel coronavirus. Such non-specific immune reactions, however, are not only ineffective but take up immunological resources and encourage unnecessary inflammation. “It seems completely random,” Akiko Iwasaki, a professor in the Departments of Immunobiology and Molecular, Cellular, and Developmental Biology at Yale University who directed this study, told The Atlantic. “The immune system almost seems confused as to what it’s supposed to be making.”

What if the immune system already knows what immune cells to deploy?

If that’s the case, immune reactions would be more specific. Unwanted inflammation and multi-organ damage would happen less often. And the host would stand a good chance at overcoming Covid-19.

Such non-specific immune reactions, however, are not only ineffective but consume immunological resources and encourage unnecessary inflammation.

Five different cohort studies from the Netherlands, US, UK, Germany, and Singapore reported that 20–60% of individuals never faced Covid-19 had T-cells that reacted against SARS-CoV-2 spike and other important proteins, but to a lesser extent than that of recovered Covid-19 patients. Still, it shows that T-cells profiles of unexposed and exposed people to Covid-19 can overlap. Seems like in these subsets of people naive to Covid-19, their immune system knows what to do. How?

All five research groups suggest that cross-immunity from prior exposure to human coronaviruses (HCoVs) — such as HCoV-OC43, HCoV-HKU1, HCoV-NL63, or HCoV-229E — that causes common cold might be the reason.

Does cross-immunity of T-cells really exist?

In a published paper in Science on August, academics at the La Jolla Institute for Immunology in California sought to find out if prior common cold infection provides cross-immunity against Covid-19. Daniela Weiskopf, an assistant professor who have spent 11 years researching on T-cells, and Alessandro Sette, a professor with 35 years of immunology research experience, both led the study.

In this study, the immunologists isolated immune cells from 88 donors who never had SARS-CoV-2. They mixed those immune cells with 142 distinct SARS-CoV-2 proteins — of which 66 from the spike and 76 other relevant proteins — and monitored the immune reactions over two weeks. Results showed that each donor recognized an average of 11 SARS-CoV-2 proteins (range of 1–33; median of 6.5). And 54% of donors recognized parts of the SARS-CoV-2 spike protein, the key immunogenic and virulence factor.

Such cross-immunity boils down to grasping an evolutionary concept that natural selection builds on existing biological entities. Thus, some parts of SARS-CoV-2 would still be similar to previous coronaviruses.

Next, using bioinformatics, the researchers showed that SARS-CoV-2 proteins recognized by T-cells shared a substantial sequence similarity to proteins of human coronaviruses (HCoVs). Accordingly, nearly all donors had antibodies against common cold-causing HCoVs. To further confirm cross-immunity, they constructed HCoVs proteins and repeated what they did with SARS-CoV-2 proteins. And, indeed, the donors’ T-cells reacted against HCoVs proteins too, as they did with SARS-CoV-2 proteins. To validate cross-immunity again, the immunologists exposed cultured T-cells to HCoVs proteins. About one-quarter (10/42) of these ‘trained’ T-cells cultures then successfully displayed cross-immunity against SARS-CoV-2 proteins.

In sum, this exhaustive study used different research methods to prove a point — that coronavirus cross-immunity in T-cells exist.

When T-cells outsmarted SARS-CoV-2

“We have now proven that, in some people, pre-existing T cell memory against common cold coronaviruses can cross-recognize SARS-CoV-2, down to the exact molecular structures,” Professor Weiskopf said in a news release. “This could help explain why some people show milder symptoms of the disease while others get severely sick.”

By committing HCoVs protein structures to memory, the T-cells can outsmart SARS-CoV-2 that is entirely novel to the immune system. Such cross-immunity boils down to grasping an evolutionary concept that natural selection builds on existing biological entities. Thus, some parts of SARS-CoV-2 would still be similar to previous coronaviruses. And it is these parts that confer cross-immunity.

Ultimately, an efficient adaptive immune response is needed to overcome infections the innate immunity cannot handle. And T-cells have a final say on that.

“Having a strong T cell response, or a better T cell response may give you the opportunity to mount a much quicker and stronger response,” Professor Sette added. “We knew there was pre-existing reactivity, and this study provides very strong direct molecular evidence that memory T cells can ‘see’ sequences that are very similar between common cold coronaviruses and SARS-CoV-2.”

Why T-cells?

T-cells and B-cells comprise the adaptive immune system that takes time to prepare for a specific pathogen. After fighting infections, T-cells and B-cells also keep a ‘memory’ of that pathogen, so that it can activate quicker the next time it sees the same pathogen. In contrast, the innate immune system — such as neutrophils, macrophages, antimicrobial peptides, mucus, skin barrier, etc. — is fast and respond the same to all pathogens. Think of innate immunity as frontline soldiers and adaptive immunity as snipers, suggests Bo Stapler, MD.

Ultimately, an efficient adaptive immune response is needed to overcome infections the innate immunity cannot handle. And T-cells have a final say on that. T-cells have two types: (1) Cytotoxic CD8+ T-cells that kill infected cells. (2) Helper CD4+ T-cells that help B-cells to produce antibodies and other immune cells to do its job better. Cripple the helper T-cells, like what HIV does, and the whole immune system functions less effectively.

Hence, it is not an issue if antibodies wane like they usually do (perhaps as to not expend unnecessary resources) as long as T-cells retain their memory, which they did even from prior common HCoVs. As follows, the age-related shrinkage of the thymus gland — where T-cells mature — may be one reason why old age alone is a major risk factor for severe Covid-19.

Short Abstract

Many cohort studies found that people who never encountered Covid-19 had T-cells that reacted against SARS-CoV-2 proteins. Researchers, thus, suggest that cross-immunity might be at play: Prior exposures to human coronaviruses (HCoVs) that causes common cold could prime the T-cells to mount a more effective immune response to SARS-CoV-2. A recent meticulous study has just confirmed that cross-immunity exists in T-cells. So, in certain cases, T-cells outsmarted an enemy it has never seen by learning from its predecessors. This prevents the immune system from mounting unspecific responses (e.g., anti-fungal, anti-parasitic, etc.) and unnecessary inflammation.