The results of a study led by Northern Arizona University and the Translational Genomics Research Institute (TGen), an affiliate of City of Hope, suggest the immune systems of people infected with COVID-19 may rely on antibodies created during infections from earlier coronaviruses to help fight the disease.
COVID-19 isn’t humanity’s first encounter with a coronavirus, so named because of the corona, or crown-like, protein spikes on their surface. Before SARS-CoV-2 – the virus that causes COVID-19 – humans have navigated at least 6 other types of coronaviruses.
The study sought to understand how coronaviruses (CoVs) ignite the human immune system and conduct a deeper dive on the inner workings of the antibody response. The published findings appear today in the journal Cell Reports Medicine.
“Our results suggest that the COVID-19 virus may awaken an antibody response that existed in humans prior to our current pandemic, meaning that we might already have some degree of pre-existing immunity to this virus.” said John Altin, Ph.D., an Assistant Professor in TGen’s infectious disease branch and the study’s senior author.
This knowledge could help researchers design new diagnostics, evaluate the healing powers of convalescent plasma, develop new therapeutic treatments, and – importantly – help design future vaccines or monoclonal antibody therapies capable of protecting against mutations that may occur in the COVID-19 virus.
The researchers used a tool called PepSeq to finely map antibody responses to all human-infecting coronaviruses. PepSeq is a novel technology being developed at TGen and NAU that allows for the construction of highly diverse pools of peptides (short chains of amino acids) bound to DNA tags. When combined with high-throughput sequencing, these PepSeq molecule pools allow for deep interrogation of the antibody response to viruses.
“The data generated using PepSeq allowed for broad characterization of the antibody response in individuals recently infected with SARS-CoV-2 compared with those of individuals exposed only to previous coronaviruses that now are widespread in human populations,” said Jason Ladner, Ph.D., an Assistant Professor at NAU’s Pathogen and Microbiome Institute, which combines the academic genomic research focus of NAU and the translational genomics capacity of TGen. Dr. Ladner is the study’s lead author.
Besides SARS-CoV-2, researchers examined the antibody responses from two other potentially deadly coronaviruses: MERS-CoV, which caused the 2012 outbreak in Saudi Arabia of Middle East Respiratory Syndrome; and SARS-CoV-1, the first pandemic coronavirus that caused the 2003 outbreak in Asia of Severe Acute Respiratory Syndrome.
All three are examples of coronaviruses that infect animals, but evolved to make people sick and became new human pathogens.
In addition to characterizing antibodies that recognize SARS-CoV-2, they also examined the antibody responses of four older coronaviruses: alphacoronavirus 229E; alphacoronavirus NL63; betacoronavirus OC43; and betacoronavirus HKU1. These so called “common” coronaviruses are endemic throughout human populations, but usually are not deadly and cause mild upper respiratory infections similar to those of the common cold.
By comparing patterns of reactivity against these different coronaviruses, the researchers demonstrated that SARS-CoV-2 could summon immune system antibodies originally generated in response to past coronavirus infections. This cross-reactivity occurred at two sites in the SARS-CoV-2 Spike protein; the protein on the surface of virus particles that attaches to ACE2 proteins on human cells to facilitate cell entry and infection.
“Our findings highlight sites at which the SARS-CoV-2 response appears to be shaped by previous coronavirus exposures, and which have potential to raise broadly-neutralizing antibodies.
We further demonstrate that these cross-reactive antibodies preferentially bind to endemic coronavirus peptides, suggesting that the response to SARS-CoV-2 at these regions may be constrained by previous coronavirus exposure,” said Dr. Altin, adding that more research is needed to understand the implications of these findings.
The findings could help explain the widely varying reactions COVID-19 patients have to the disease; from mild to no symptoms, to severe infections requiring hospitalization, and often resulting in death.
It’s also possible that differences in the pre-existing antibody response identified by this study could help to explain some of the difference in how severely COVID-19 disease manifests in old versus young people, who will have different histories of infections with the common coronaviruses.
The study—Epitope-resolved profiling of the SARS-CoV-2 antibody response identifies cross-reactivity with endemic human coronaviruses—was published in Cell Reports Medicine.
Impact of Frequent Respiratory Infections in Childhood and Virologic and Immunologic Interference
Numerous studies (21⇓–23) show that children younger than 2 y of age have five or more respiratory infections per year, and spend a median of 44 d with mild upper respiratory illnesses (21).
The activation of adaptive immunity to common coronaviruses as well as the activation of the innate immune system in the respiratory tract may indeed provide some protection from microbial infection, including SARS-CoV-2. The frequent respiratory infections in children may provide further clues to why children are resistant. One line of reasoning is based on the phenomenon of viral interference. A second line of reasoning is based on the concept of immune interference.
Viral Interference.
Often, children are infected by more than one viral agent (21, 22). Viral interference is a well-known phenomenon where one virus interferes with the replication of a second virus (23). There is some evidence for coinfections in COVID-19 patients, including coinfection with other coronaviruses (24, 25). Kim et al. (24) reported on both hospitalized and nonhospitalized cases from Northern California, including children.
They found more than 20% were positive for a second viral infection, including infection with other coronaviruses. In contrast, Nowak et al. (25) reported concurrent viral infection in only 3% of 1,204 SARS-CoV-2−positive patients from the New York metropolitan area who were also tested with a respiratory virus panel or a test for influenza and respiratory syncytial virus (RSV).
In comparison, of 7,418 patients who tested negative for SARS- CoV-2, 845 were tested with the same multiplex panels, and 13% were positive for at least one non-SARS-CoV-2 respiratory viral pathogen (25). The increase in at least one non-SARS-CoV-2 viral pathogen in those who tested negative for SARS-CoV-2 may be due, in part, to viral interference.
An intriguing potential mechanism of resistance in children is that common coronaviruses associated with mild illnesses like colds and more severe illness like croup and bronchiolitis are associated with decreased expression of ACE2. For example, human coronavirus (HCoV) NL63, associated with common colds and croup, induces a down-regulation of ACE2 (26).
A reduction in the viral receptor for SARS-CoV-2 therefore might help explain why children who carry such viruses in their nose and upper portions of their respiratory tracts are hospitalized less frequently than adults. The first site of encounter in the respiratory tract for the SARS-CoV-2 is in the nose.
Investigators studying a cohort of 305 patients aged 4 y to 60 y found that “older children (10 y to 17 y old; n = 185), young adults (18 y to 24 y old; n = 46), and adults (≥25 y old; n = 29) all had higher expression of ACE2 in the nasal epithelium compared with younger children (4 y to 9 y old; n = 45)” (27).
Despite diminished expression of ACE2 and/or TMPRSS2 in children, “symptomatic infants have higher nasopharyngeal SARS-CoV-2 viral loads at presentation but develop less severe disease than older children and adolescents” (28). Moreover, children less than 5 y old “with mild to moderate COVID-19 have high amounts of SARS-CoV-2 viral RNA in their nasopharynx compared with older children and adults” (29).
Taken together, these data imply that, although the viral load in the nasopharynx may be higher in symptomatic children, overall, children remain markedly more resistant to viral infection of the lower respiratory tract leading to COVID-19. All this raises the likelihood that, although children are, fortunately, less susceptible to viral infection of the lungs, they can still serve as good disseminators of the SARS-CoV-2 virus that lurks in their nasal mucosa.
Detailed contact tracing from the Korean CDC revealed that household contacts of COVID-19−positive children ages 10 y to 19 y were the most likely to become infected with the SARS-CoV-2 virus compared to household contacts of people of all other ages. In contrast, household contacts of positive children aged 0 y to 9 y were the least likely to become infected.
Taken together, these data need further substantiation, and might have implications for spread of infection at home, in daycare, and in schools (30). These data all emphasize that there is much to learn and to consider on the spread from children in various environments. It will also be important to stratify children by age, as infants, young children, and adolescents have different propensities for communicating viral infection.
Immunological Interference.
IFNs, first described in 1957 by Isaacs and Lindemann, bind to three distinct types of IFN receptors (31). Mapping of immune response modules in the respiratory tract shows that gene modules triggered by both type 1 and type 2 IFN responses are prominent (17, 18, 32, 33). The type 1 IFN response is vital for viral killing.
Type 1 IFN, however, stimulates expression of the ACE2 receptor for the SARS-CoV-2 virus (33). Thus, the virus drives an increase in type 1 IFN expression, which then enhances expression of its receptor in the airway (33). In contrast, coronaviruses that frequently infect children with common colds down-regulate ACE2 as described above (26).
Thus, children may benefit from a virtuous cycle with decreased ACE2 leading to less induction of the IFN response, which, in turn, further attenuates ACE2 expression. In contrast, adults suffer from a vicious cycle in which increased ACE2 expression drives a more robust IFN response.
The adaptive immune response to common coronavirus infection in children could provide some protection to COVID-19 since they share considerable degrees of homology with coronaviruses associated with the common cold. For example, spike proteins of the common HCoV share 30% amino acid identity with these viruses when one performs Basic Local Alignment Search Tool searches comparing these viruses. A detailed mapping of known T and B cell epitopes on SARS-CoV-2 indicates that adaptive immune reactivity at the T cell and antibody level targets not just the spike region but also other viral proteins (34).
A study in adult donors, age currently greater than 20 y, tested whether there was detectable immunity to SARS-CoV-2 and to common cold viruses attributed to coronavirus strains HCoV-OC43, HCoV-HKU1, HCoV-NL63, and HCoV-229E. Donors were recruited between 2015 and 2018, obviating exposure to SARS-CoV-2.
Unexposed donors had T cell immunity to both spike and nonspike proteins in SARS-CoV-2 (34). The immunity may have emanated from shared regions on the common cold virus and SARS-CoV-2. Investigators tested immunity to one betacorononavirus HCoV-OC43 and to one alphacoronavirus NL63, and showed that these unexposed donors, n = 11, all had IgG to the receptor-binding domain of these common cold viruses.
These nonexposed donors also had vigorous T cell responses to both spike and nonspike proteins in SARS-CoV-2 (35). Additional studies have been reported demonstrating widespread immunity in healthy individuals to cross-reactive regions of SARS-CoV-2 that share peptide sequence homology with endemic coronaviruses that cause common colds like HCoV-OC43, HCoV-229E, HCoV-NL63, and HCoV-HKU1 (36, 37).
Humoral, antibody immunity to SARS-CoV-2 is widely detected in individuals, including children, who were not exposed to SARS-CoV-2 (38). Immunity to earlier exposures to both alpha and beta coronaviruses may thus engender protective humoral and cellular immunity for children who are heavily exposed to these common cold viruses.
A publication (39) from the Department of Defense examining the effect of the 2017–2018 seasonal influenza vaccine on respiratory infections produced some intriguing results. Investigators showed that the seasonal influenza immunization protected against influenza, as it was intended to do, and protected against some other respiratory viruses.
However, they noted a small but statistically significant increase in individuals testing positive to metapneumovirus and coronaviruses. If future influenza vaccines, for example the 2020–2021 seasonal influenza vaccine, also provide increased occurrence of common coronaviruses, this phenomenon may actually afford some protection to SARS-CoV-2. Recent studies show that those with immunity to common coronaviruses do have adaptive immunity to SARS-CoV-2 via the mechanism of cross-reactive immunity (35⇓–37).
There is some precedent for this phenomenon. Some immunizations induce protection against other infections outside of the intended target of the vaccine itself (40). A study from the Mayo Clinic indicated that “polio, Hemophilus influenzae type-B (HIB), measles-mumps-rubella (MMR), varicella, pneumococcal conjugate (PCV13), geriatric flu, and hepatitis A/hepatitis B (HepA-HepB) vaccines administered in the past 1, 2, and 5 y are associated with decreased SARS-CoV-2 infection rates” (41).
Some antiviral vaccines like the MMR vaccine contain components that have structural similarities with SARS-CoV-2 (42, 43). There is a 29% amino acid sequence homology between the ADP ribose-1-phosphatase domains of SARS-CoV-2 and rubella virus, including surface-exposed conserved residues shared between SARS-CoV-2 and the attenuated rubella virus in MMR (42).
Patients with COVID-19 infection had raised levels of rubella IgG, but did not have increased rubella IgM, nor did they have increased levels of antibody to varicella zoster. The investigators interpret these results as indicative of a cross-reactive recall antibody response, common to regions shared between rubella and SARS-CoV-2, that may modulate the course of disease in COVID-19 (42). Whether or not such an immune response is protective or whether such an immune response might potentially enhance disease are outcomes under investigation (42).
A Surprising Potential Protective Benefit of Th2 Immunity in Children
There are three major arms of the immune response characteristics of human T helper cells, named Th1, Th2, and Th17 (33). The Th1 arm described above is mediated by gamma IFN. The Th2 arm is associated with allergic disease, and is mediated by IL-4, IL-5, and IL-13 (44). Sajuthi et al. (33) reported on gene expression studies on 695 children with asthma and healthy controls from the Genes-Environment & Admixture in Latino Americans study, an ongoing case-control study of asthma in Latino children and adolescents.
They found that TMPRSS2 is part of a mucus secretory network, driven by Th2 inflammation via the actions of IL-13 (33). They found that Th2 responses driven by IL-4, IL-5, and IL-13 “dramatically” reduced ACE2 in the respiratory tract and are associated with better clinical outcomes with COVID-19, while the type 1 IFN response to respiratory viruses increased ACE2 expression (33).
Th2 cytokines drive an increase of a cell type called the eosinophil in the blood and tissues. Eosinophilia is a hallmark of Th2 inflammation in the airways, most notably in asthma (33, 45). Sajuthi et al. (33) concluded that, at least “provisionally… T[h]2 inflammation may predispose individuals to experience better COVID-19 outcomes through a decrease in airway levels of ACE2 that override any countervailing effect from increased expression of TMPRSS2.”
It is indeed surprising that the Th2 immune type associated with allergic diseases including asthma, and with eosinophilia, provides some protection to COVID-19 in children. These findings from Sajuthi et al. (33) on 695 children and adolescents may help explain why low levels of eosinophilia were seen in fatalities in the elderly. Du et al. (45) reported that, in a study of 85 fatal COVID-19 adult subjects, 81.2% exhibited very low levels of blood eosinophils. A connection between knowledge gained in studying children (33) versus studying older adults, may help explain surprising outcomes in the elderly (45). This is one of the unexpected benefits of investigations on the “extremes of outcome” based on comparing children with the elderly populations at highest risk.
Another independent verification of the possible protective role of Th2 immunity was seen in a study on MIS-C. The very low IgE levels seen in individuals with MIS-C indicate that they may have lacked an adequate Th2 response to attenuate the increased inflammation associated with this hyperinflammatory complication in children (46).
One important caveat about the potential protective effect of eosinophilia comes from studies done 50 y ago in making a vaccine against RSV. “In 1967, infants and toddlers immunized with a formalin-inactivated vaccine against RSV experienced an enhanced form of RSV disease characterized by high fever, bronchopneumonia, and wheezing when they became infected with wild-type virus in the community.
Hospitalizations were frequent, and two immunized toddlers died upon infection with wild-type RSV. The enhanced disease was initially characterized as a ‘peribronchiolar monocytic infiltration with some excess in eosinophils’” (47). As new SARS-CoV2 vaccines are tested, the potential appearance of Th2 immunity and eosinophilia must be scrutinized through a lens of caution.
Although Th2 responses appear to be associated with some degree of protection to COVID-19, based on the experience with development of a novel vaccine to RSV 50 y ago, the dreaded development of immune enhancement, rather than immunization, must be assessed.
reference link :https://www.pnas.org/content/117/40/24620
More information: Cell Reports Medicine, DOI: 10.1016/j.xcrm.2020.100189
