Dr Lindsay Broadbent

The choice of model used to study human respiratory syncytial virus (RSV) infection is extremely important. RSV is a human pathogen that is exquisitely adapted to infection of human hosts. Rodent models, such as mice and cotton rats, are semi-permissive to RSV infection and do not faithfully reproduce hallmarks of RSV disease in humans. Furthermore, immortalized airway-derived cell lines, such as HEp-2, BEAS-2B, and A549 cells, are poorly representative of the complexity of the respiratory epithelium. The development of a well-differentiated primary pediatric airway epithelial cell models (WD-PAECs) allows us to simulate several hallmarks of RSV infection of infant airways. They therefore represent important additions to RSV pathogenesis modeling in human-relevant tissues. The following protocols describe how to culture and differentiate both bronchial and nasal primary pediatric airway epithelial cells and how to use these cultures to study RSV cytopathogenesis.

As the most important viral cause of severe respiratory disease in infants and increasing recognition as important in the elderly and immunocompromised, respiratory syncytial virus (RSV) is responsible for a massive health burden worldwide. Prophylactic antibodies were successfully developed against RSV. However, their use is restricted to a small group of infants considered at high risk of severe RSV disease. There is still no specific therapeutics or vaccines to combat RSV. As such, it remains a major unmet medical need for most individuals. The World Health Organisations International Clinical Trials Registry Platform (WHO ICTRP) and PubMed were used to identify and review all RSV vaccine, prophylactic and therapeutic candidates currently in clinical trials. This review presents an expert commentary on all RSV-specific prophylactic and therapeutic candidates that have entered clinical trials since 2008.

Airway epithelium is the primary target of many respiratory viruses. However, virus induction and antagonism of host responses by human airway epithelium remains poorly understood. To address this, we developed a model of respiratory syncytial virus (RSV) infection based on well-differentiated pediatric primary bronchial epithelial cell cultures (WD-PBECs) that mimics hallmarks of RSV disease in infants. RSV is the most important respiratory viral pathogen in young infants worldwide. We found that RSV induces a potent antiviral state in WD-PBECs that was mediated in part by secreted factors, including interferon lambda 1 (IFN-λ1)/interleukin-29 (IL-29). In contrast, type I IFNs were not detected following RSV infection of WD-PBECs. IFN responses in RSV-infected WD-PBECs reflected those in lower airway samples from RSV-hospitalized infants. In view of the prominence of IL-29, we determined whether recombinant IL-29 treatment of WD-PBECs before or after infection abrogated RSV replication. Interestingly, IL-29 demonstrated prophylactic, but not therapeutic, potential against RSV. The absence of therapeutic potential reflected effective RSV antagonism of IFN-mediated antiviral responses in infected cells. Our data are consistent with RSV nonstructural proteins 1 and/or 2 perturbing the Jak-STAT signaling pathway, with concomitant reduced expression of antiviral effector molecules, such as MxA/B. Antagonism of Jak-STAT signaling was restricted to RSV-infected cells in WD-PBEC cultures. Importantly, our study provides the rationale to further explore IL-29 as a novel RSV prophylactic. Most respiratory viruses target airway epithelium for infection and replication, which is central to causing disease. However, for most human viruses we have a poor understanding of their interactions with human airway epithelium. Respiratory syncytial virus (RSV) is the most important viral pathogen of young infants. To help understand RSV interactions with pediatric airway epithelium, we previously developed three-dimensional primary cell cultures from infant bronchial epithelium that reproduce several hallmarks of RSV infection in infants, indicating that they represent authentic surrogates of RSV infection in infants. We found that RSV induced a potent antiviral state in these cultures and that a type III interferon, interleukin IL-29 (IL-29), was involved. Indeed, our data suggest that IL-29 has potential to prevent RSV disease. However, we also demonstrated that RSV efficiently circumvents this antiviral immune response and identified mechanisms by which this may occur. Our study provides new insights into RSV interaction with pediatric airway epithelium.

Innate immune responses of airway epithelium are important defences against respiratory pathogens and allergens. Newborn infants are at greater risk of severe respiratory infections compared to older infants, while premature infants are at greater risk than full term infants. However, very little is known regarding human neonatal airway epithelium immune responses and whether age-related morphological and/or innate immune changes contribute to the development of airway disease. We collected nasal epithelial cells from 41 newborn infants (23 term, 18 preterm) within 5 days of birth. Repeat sampling was achieved for 24 infants (13 term, 11 preterm) at a median age of 12.5 months. Morphologically- and physiologically-authentic well-differentiated primary paediatric nasal epithelial cell (WD-PNEC) cultures were generated and characterised using light microscopy and immunofluorescence. WD-PNEC cultures were established for 15/23 (65%) term and 13/18 (72%) preterm samples at birth, and 9/13 (69%) term and 8/11 (73%) preterm samples at one-year. Newborn and infant WD-PNEC cultures demonstrated extensive cilia coverage, mucous production and tight junction integrity. Newborn WD-PNECs took significantly longer to reach full differentiation and were noted to have much greater proportions of goblet cells compared to one-year repeat WD-PNECs. No differences were evident in ciliated/goblet cell proportions between term- and preterm-derived WD-PNECs at birth or one-year old. We describe the successful generation of newborn-derived WD-PNEC cultures and their revival from frozen. We also compared the characteristics of WD-PNECs derived from infants born at term with those born prematurely at birth and at one-year-old. The development of WD-PNEC cultures from newborn infants provides a powerful and exciting opportunity to study the development of airway epithelium morphology, physiology, and innate immune responses to environmental or infectious insults from birth.

The airway epithelium is the primary target of respiratory syncytial virus infection. It is an important component of the antiviral immune response. It contributes to the recruitment and activation of innate immune cells from the periphery through the secretion of cytokines and chemokines. This paper provides a broad review of the cytokines and chemokines secreted from human airway epithelial cell models during respiratory syncytial virus (RSV) infection based on a comprehensive literature review. Epithelium-derived chemokines constitute most inflammatory mediators secreted from the epithelium during RSV infection. This suggests chemo-attraction of peripheral immune cells, such as monocytes, neutrophils, eosinophils, and natural killer cells as a key function of the epithelium. The reports of epithelium-derived cytokines are limited. Recent research has started to identify novel cytokines, the functions of which remain largely unknown in the wider context of the RSV immune response. It is argued that the correct choice of in vitro models used for investigations of epithelial immune functions during RSV infection could facilitate greater progress in this field.

This is the first comprehensive analysis of secretome in a hRSV-infected paediatric airway epithelium, which identified skewing of apical/basolateral abundance ratios for individual proteins, and validated three novel biomarkers (CXCL6, CXCL16 and CSF3) and a novel antiviral protein (CEACAM1). [Display omitted] Highlights •Proteome of airway secretions derived from mock- and hRSV-infected WD-PBEC cultures.•A polarised secretome in uninfected WD-PBECs, skewed in hRSV-infected cultures.•CXCL6, CXCL16, CECACAM1 and CSF3 induced only upon hRSV-infection.•Detection of CXCL6, CXCL16 and CSF3 in NPAs from hRSV-positive children. The respiratory epithelium comprises polarized cells at the interface between the environment and airway tissues. Polarized apical and basolateral protein secretions are a feature of airway epithelium homeostasis. Human respiratory syncytial virus (hRSV) is a major human pathogen that primarily targets the respiratory epithelium. However, the consequences of hRSV infection on epithelium secretome polarity and content remain poorly understood. To investigate the hRSV-associated apical and basolateral secretomes, a proteomics approach was combined with an ex vivo pediatric human airway epithelial (HAE) model of hRSV infection (data are available via ProteomeXchange and can be accessed at https://www.ebi.ac.uk/pride/ with identifier PXD013661). Following infection, a skewing of apical/basolateral abundance ratios was identified for several individual proteins. Novel modulators of neutrophil and lymphocyte activation (CXCL6, CSF3, SECTM1 or CXCL16), and antiviral proteins (BST2 or CEACAM1) were detected in infected, but not in uninfected cultures. Importantly, CXCL6, CXCL16, CSF3 were also detected in nasopharyngeal aspirates (NPA) from hRSV-infected infants but not healthy controls. Furthermore, the antiviral activity of CEACAM1 against RSV was confirmed in vitro using BEAS-2B cells. hRSV infection disrupted the polarity of the pediatric respiratory epithelial secretome and was associated with immune modulating proteins (CXCL6, CXCL16, CSF3) never linked with this virus before. In addition, the antiviral activity of CEACAM1 against hRSV had also never been previously characterized. This study, therefore, provides novel insights into RSV pathogenesis and endogenous antiviral responses in pediatric airway epithelium.

Respiratory syncytial virus (RSV) infections remain a major cause of respiratory disease and hospitalizations among infants. Infection recurs frequently and establishes a weak and short-lived immunity. To date, RSV immunoprophylaxis and vaccine research is mainly focused on the RSV fusion (F) protein, but a vaccine remains elusive. The RSV F protein is a highly conserved surface glycoprotein and is the main target of neutralizing antibodies induced by natural infection. Here, we analyzed an internalization process of antigen-antibody complexes after binding of RSV-specific antibodies to RSV antigens expressed on the surface of infected cells. The RSV F protein and attachment (G) protein were found to be internalized in both infected and transfected cells after the addition of either RSV-specific polyclonal antibodies (PAbs) or RSV glycoprotein-specific monoclonal antibodies (MAbs), as determined by indirect immunofluorescence staining and flow-cytometric analysis. Internalization experiments with different cell lines, well-differentiated primary bronchial epithelial cells (WD-PBECs), and RSV isolates suggest that antibody internalization can be considered a general feature of RSV. More specifically for RSV F, the mechanism of internalization was shown to be clathrin dependent. All RSV F-targeted MAbs tested, regardless of their epitopes, induced internalization of RSV F. No differences could be observed between the different MAbs, indicating that RSV F internalization was epitope independent. Since this process can be either antiviral, by affecting virus assembly and production, or beneficial for the virus, by limiting the efficacy of antibodies and effector mechanism, further research is required to determine the extent to which this occurs and how this might impact RSV replication. Current research into the development of new immunoprophylaxis and vaccines is mainly focused on the RSV F protein since, among others, RSV F-specific antibodies are able to protect infants from severe disease, if administered prophylactically. However, antibody responses established after natural RSV infections are poorly protective against reinfection, and high levels of antibodies do not always correlate with protection. Therefore, RSV might be capable of interfering, at least partially, with antibody-induced neutralization. In this study, a process through which surface-expressed RSV F proteins are internalized after interaction with RSV-specific antibodies is described. One the one hand, this antigen-antibody complex internalization could result in an antiviral effect, since it may interfere with virus particle formation and virus production. On the other hand, this mechanism may also reduce the efficacy of antibody-mediated effector mechanisms toward infected cells.

La/SS-B (or La) is a 48 kDa RNA-binding protein and an autoantigen in autoimmune disorders such as systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS). La involvement in regulating the type I interferon (IFN) response is controversial - acting through both positive and negative regulatory mechanisms; inhibiting the IFN response and enhancing viral growth, or directly inhibiting viral replication. We therefore sought to clarify how La regulates IFN production in response to viral infection. ShRNA knockdown of La in HEK 293 T cells increased Sendai virus infection efficiency, decreased IFN-beta, IFN-lambda 1, and interferon-stimulated chemokine gene expression. In addition, knockdown attenuated CCL-5 and IFN-lambda 1 secretion. Thus, La has a positive role in enhancing type I and type III IFN production. Mechanistically, we show that La directly binds RIG-I and have mapped this interaction to the CARD domains of RIG-I and the N terminal domain of La. In addition, we showed that this interaction is induced following RIG-I activation and that overexpression of La enhances RIG-I-ligand binding. Together, our results demonstrate a novel role for La in mediating RIG-I-driven responses downstream of viral RNA detection, ultimately leading to enhanced type I and III IFN production and positive regulation of the anti-viral response.

Respiratory syncytial virus (RSV) causes severe lower respiratory tract infections in young infants. There are no RSV-specific treatments available. Ablynx has been developing an anti-RSV F-specific nanobody, ALX-0171. To characterize the therapeutic potential of ALX-0171, we exploited our well-differentiated primary pediatric bronchial epithelial cell (WD-PBEC)/RSV infection model, which replicates several hallmarks of RSV disease in vivo. Using 2 clinical isolates (BT2a and Memphis 37), we compared the therapeutic potential of ALX-0171 with that of palivizumab, which is currently prescribed for RSV prophylaxis in high-risk infants. ALX-0171 treatment (900 nM) at 24 h postinfection reduced apically released RSV titers to near or below the limit of detection within 24 h for both strains. Progressively lower doses resulted in concomitantly diminished RSV neutralization. ALX-0171 was approximately 3-fold more potent in this therapeutic RSV/WD-PBEC model than palivizumab (mean 50% inhibitory concentration [IC50] = 346.9 to 363.6 nM and 1,048 to 1,090 nM for ALX-0171 and palivizumab, respectively), irrespective of the clinical isolate. The number of viral genomic copies (GC) was determined by quantitative reverse transcription-PCR (RT-qPCR), and the therapeutic effect of ALX-0171 treatment at 300 and 900 nM was found to be considerably lower and the number of GCs reduced only moderately (0.62 to 1.28 log10 copies/ml). Similar findings were evident for palivizumab. Therefore, ALX-0171 was very potent at neutralizing RSV released from apical surfaces but had only a limited impact on virus replication. The data indicate a clear disparity between viable virus neutralization and GC viral load, the latter of which does not discriminate between viable and neutralized RSV. This report validates the RSV/WD-PBEC model for the preclinical evaluation of RSV antivirals.

The culture of differentiated human airway epithelial cells allows the study of pathogen-host interactions and innate immune responses in a physiologically relevant in vitro model. As the use of primary cell culture has gained popularity the availability of the reagents needed to generate these cultures has increased. In this study we assessed two different media, Promocell and PneumaCult, during the differentiation and maintenance of well-differentiated primary nasal epithelial cell cultures (WD-PNECs). We compared and contrasted the consequences of these media on WD-PNEC morphological and physiological characteristics and their responses to respiratory syncytial virus (RSV) infection. We found that cultures generated using PneumaCult resulted in greater total numbers of smaller, tightly packed, pseudostratified cells. However, cultures from both media resulted in similar proportions of ciliated and goblet cells. There were no differences in RSV growth kinetics, although more ciliated cells were infected in the PneumaCult cultures. There was also significantly more IL-29/IFN lambda 1 secreted from PneumaCult compared to Promocell cultures following infection. In conclusion, the type of medium used for the differentiation of primary human airway epithelial cells may impact experimental results.

SARS-CoV-2 can efficiently infect both children and adults, albeit with morbidity and mortality positively associated with increasing host age and presence of co-morbidities. SARS-CoV-2 continues to adapt to the human population, resulting in several variants of concern (VOC) with novel properties, such as Alpha and Delta. However, factors driving SARS-CoV-2 fitness and evolution in paediatric cohorts remain poorly explored. Here, we provide evidence that both viral and host factors co-operate to shape SARS-CoV-2 genotypic and phenotypic change in primary airway cell cultures derived from children. Through viral whole-genome sequencing, we explored changes in genetic diversity over time of two pre-VOC clinical isolates of SARS-CoV-2 during passage in paediatric well-differentiated primary nasal epithelial cell (WD-PNEC) cultures and in parallel, in unmodified Vero-derived cell lines. We identified a consistent, rich genetic diversity arising in vitro, variants of which could rapidly rise to near fixation within two passages. Within isolates, SARS-CoV-2 evolution was dependent on host cells, with paediatric WD-PNECs showing a reduced diversity compared to Vero (E6) cells. However, mutations were not shared between strains. Furthermore, comparison of both Vero-grown isolates on WD-PNECs disclosed marked growth attenuation mapping to the loss of the polybasic cleavage site (PBCS) in Spike, while the strain with mutations in Nsp12 (T293I), Spike (P812R) and a truncation of Orf7a remained viable in WD-PNECs. Altogether, our work demonstrates that pre-VOC SARS-CoV-2 efficiently infects paediatric respiratory epithelial cells, and its evolution is restrained compared to Vero (E6) cells, similar to the case of adult cells. We highlight the significant genetic plasticity of SARS-CoV-2 while uncovering an influential role for collaboration between viral and host cell factors in shaping viral evolution and ultimately fitness in human respiratory epithelium.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the coronavirus disease-19 (COVID-19) pandemic, was identified in late 2019 and caused >5 million deaths by February 2022. To date, targeted antiviral interventions against COVID-19 are limited. The spectrum of SARS-CoV-2 infection ranges from asymptomatic to fatal disease. However, the reasons for varying outcomes to SARS-CoV-2 infection are yet to be elucidated. Here we show that an endogenously activated interferon lambda (IFNλ1) pathway leads to resistance against SARS-CoV-2 infection. Using a well-differentiated primary nasal epithelial cell (WD-PNEC) culture model derived from multiple adult donors, we discovered that susceptibility to SARS-CoV-2 infection, but not respiratory syncytial virus (RSV) infection, varied. One of four donors was resistant to SARS-CoV-2 infection. High baseline IFNλ1 expression levels and associated interferon stimulated genes correlated with resistance to SARS-CoV-2 infection. Inhibition of the JAK/STAT pathway in WD-PNECs with high endogenous IFNλ1 secretion resulted in higher SARS-CoV-2 titres. Conversely, prophylactic IFNλ treatment of WD-PNECs susceptible to infection resulted in reduced viral titres. An endogenously activated IFNλ response, possibly due to genetic differences, may be one explanation for the differences in susceptibility to SARS-CoV-2 infection in humans. Importantly, our work supports the continued exploration of IFNλ as a potential pharmaceutical against SARS-CoV-2 infection.

<h1 class="legacy">Haven’t had COVID yet? It could be more than just luck</h1> <figure>  <img src="https://images.theconversation.com/files/463952/original/file-20220518-11-i1zy58.jpg?ixlib=rb-1.1.0&rect=0%2C14%2C4768%2C3160&q=45&auto=format&w=754&fit=clip" />   <figcaption>         <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/london-uk-9-july-2021-crowd-2016939578">I Wei Huang/Shutterstock</a></span>   </figcaption> </figure><span><a href="https://theconversation.com/profiles/lindsay-broadbent-1009352">Lindsay Broadbent</a>, <em><a href="https://theconversation.com/institutions/queens-university-belfast-687">Queen's University Belfast</a></em></span><p>We all know a few of those lucky people who, somehow, have managed to avoid ever catching COVID. Perhaps you’re one of them. Is this a Marvel-esque superpower? Is there any scientific reason why a person might be resistant to becoming infected, when the virus seems to be everywhere? Or is it simply luck?</p><p>More than <a href="https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/articles/coronaviruscovid19latestinsights/infections#infections">60% of people</a> in the UK have tested positive for COVID at least once. However, the number of people who have actually been infected with SARS-CoV-2, the virus that causes COVID-19, is thought to be higher. The calculated rate of <a href="https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2787098">asymptomatic infections</a> varies depending on the study, though most agree it’s fairly common. </p><p>But even taking into account people who have had COVID and not realised it, there is still likely a group of people who never have. The reason why some people appear immune to COVID is one question that has persisted throughout the pandemic. As with so much in science, there isn’t (yet) one simple answer. </p><p>We can probably dismiss the Marvel-esque superpower theory. But science and luck likely both have a role to play. Let’s take a look.</p><p>The simplest explanation is that these people have never come into contact with the virus.</p><p>This could certainly be the case for people who have been shielding during the pandemic. People at <a href="https://www.bmj.com/content/369/bmj.m1985">significantly greater risk</a> of severe disease, such as those with chronic heart or lung conditions, have had a tough couple of years. </p><p>Many of them continue to take precautions to avoid potential exposure to the virus. Even with additional safety measures, many of these people have ended up with COVID. </p><p>Due to the high level of community transmission, particularly with the extremely transmissible omicron variants, it’s very unlikely that someone going to work or school, socialising and shopping hasn’t been near someone infected with the virus. Yet there are people who have experienced high levels of exposure, such as hospital workers or family members of people who have had COVID, who have somehow managed to avoid testing positive.</p><p>We know from several studies vaccines not only reduce the risk of severe disease, but they can also cut the chance of household transmission of SARS-CoV-2 by <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262621/">about half</a>. So certainly vaccination could have helped some close contacts avoid becoming infected. However, it’s important to note that these studies were done pre-omicron. The data we have on the effect of vaccination on omicron transmission is still limited.</p><h2>Some theories</h2><p>One theory around why certain people have avoided infection is that, although they are exposed to the virus, it fails to establish an infection even after gaining entry to the airways. This could be due to a lack of the <a href="https://www.nature.com/articles/s41588-021-01006-7">receptors needed</a> for SARS-CoV-2 to gain access to cells.</p><p>Once a person does become infected, researchers have identified that differences in the <a href="https://www.sciencedirect.com/science/article/pii/S1931312820302365?via%3Dihub">immune response</a> to SARS-CoV-2 play a role in determining the <a href="https://www.nature.com/articles/s41586-020-2588-y">severity of symptoms</a>. It is possible that a quick and robust immune response could prevent the virus from replicating to any great degree in the first instance.</p><p>The efficacy of our immune response to infection is largely defined by our age and our <a href="https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-018-0568-8">genetics</a>. That said, a healthy lifestyle certainly helps. For example, we know that <a href="https://pubmed.ncbi.nlm.nih.gov/16497887/">vitamin D deficiency</a> can increase the risk of certain infections. Not getting <a href="https://www.nature.com/articles/s42003-021-02825-4">enough sleep</a> can also have a detrimental effect on our body’s ability to fight invading pathogens.</p><figure class="align-center ">      <img alt="An illustration of SARS-CoV-2, the coronavirus that causes COVID-19." src="https://images.theconversation.com/files/463953/original/file-20220518-19-cupowl.jpg?ixlib=rb-1.1.0&amp;q=45&amp;auto=format&amp;w=754&amp;fit=clip" srcset="https://images.theconversation.com/files/463953/original/file-20220518-19-cupowl.jpg?ixlib=rb-1.1.0&amp;q=45&amp;auto=format&amp;w=600&amp;h=338&amp;fit=crop&amp;dpr=1 600w, https://images.theconversation.com/files/463953/original/file-20220518-19-cupowl.jpg?ixlib=rb-1.1.0&amp;q=30&amp;auto=format&amp;w=600&amp;h=338&amp;fit=crop&amp;dpr=2 1200w, https://images.theconversation.com/files/463953/original/file-20220518-19-cupowl.jpg?ixlib=rb-1.1.0&amp;q=15&amp;auto=format&amp;w=600&amp;h=338&amp;fit=crop&amp;dpr=3 1800w, https://images.theconversation.com/files/463953/original/file-20220518-19-cupowl.jpg?ixlib=rb-1.1.0&amp;q=45&amp;auto=format&amp;w=754&amp;h=424&amp;fit=crop&amp;dpr=1 754w, https://images.theconversation.com/files/463953/original/file-20220518-19-cupowl.jpg?ixlib=rb-1.1.0&amp;q=30&amp;auto=format&amp;w=754&amp;h=424&amp;fit=crop&amp;dpr=2 1508w, https://images.theconversation.com/files/463953/original/file-20220518-19-cupowl.jpg?ixlib=rb-1.1.0&amp;q=15&amp;auto=format&amp;w=754&amp;h=424&amp;fit=crop&amp;dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">      <figcaption>       <span class="caption">The SARS-CoV-2 virus needs to attach to receptors to gain access to our cells.</span>       <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/sarscov2-viruses-binding-ace2-receptors-on-1687909009">Kateryna Kon/Shutterstock</a></span>      </figcaption>     </figure><p>Scientists studying the <a href="https://www.covidhge.com/">underlying causes</a> of severe COVID have identified a genetic cause in nearly <a href="https://covid19.nih.gov/news-and-stories/decoding-genetics-behind-covid19-infection">20% of critical cases</a>. Just as genetics could be one determining factor of disease severity, our genetic makeup may also hold the key to resistance to SARS-CoV-2 infection.</p><p>I research SARS-CoV-2 infection on nasal cells from human donors. We grow these cells on plastic dishes which we can then add virus to and investigate how the cells respond. During our research we found one donor whose cells <a href="https://journals.plos.org/plosone/article/comments?id=10.1371/journal.pone.0266412">could not be infected</a> with SARS-CoV-2.</p><p>We discovered some really interesting genetic mutations, including several involved with the body’s immune response to infection, that could explain why. A mutation we identified in a gene involved with sensing the presence of a virus has previously been shown to confer <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4001117/">resistance to HIV</a> infection. Our research is on a small number of donors and highlights that we’re still only scraping the surface of research into genetic susceptibility or resistance to infections. </p><p>There’s also the possibility that previous infection with other types of coronaviruses results in <a href="https://www.nature.com/articles/s41467-021-27674-x">cross-reactive immunity</a>. This is where our immune system may recognise SARS-CoV-2 as being similar to a recent invading virus and launch an immune response. There are <a href="https://theconversation.com/coronaviruses-a-brief-history-135506">seven coronaviruses</a> that infect humans: four that cause the common cold, and one each that cause Sars (severe acute respiratory syndrome), Mers (Middle East respiratory syndrome) and COVID.</p><p>How long-lasting this immunity may be is another question. Seasonal coronaviruses that circulated pre-2020 were able to <a href="https://www.nature.com/articles/s41591-020-1083-1">reinfect</a> the same people after 12 months. </p><p>If you’ve managed to avoid COVID to date, maybe you do have natural immunity to SARS-CoV-2 infection, or perhaps you’ve just been lucky. Either way, it’s sensible to continue to take precautions against this virus that we still know so little about.<!-- Below is The Conversation's page counter tag. Please DO NOT REMOVE. --><img src="https://counter.theconversation.com/content/181708/count.gif?distributor=republish-lightbox-basic" alt="The Conversation" width="1" height="1" style="border: none !important; box-shadow: none !important; margin: 0 !important; max-height: 1px !important; max-width: 1px !important; min-height: 1px !important; min-width: 1px !important; opacity: 0 !important; outline: none !important; padding: 0 !important" /><!-- End of code. If you don't see any code above, please get new code from the Advanced tab after you click the republish button. The page counter does not collect any personal data. More info: https://theconversation.com/republishing-guidelines --></p><p><span><a href="https://theconversation.com/profiles/lindsay-broadbent-1009352">Lindsay Broadbent</a>, Research Fellow, School of Medicine, Dentistry and Biomedical Sciences, <em><a href="https://theconversation.com/institutions/queens-university-belfast-687">Queen's University Belfast</a></em></span></p><p>This article is republished from <a href="https://theconversation.com">The Conversation</a> under a Creative Commons license. Read the <a href="https://theconversation.com/havent-had-covid-yet-it-could-be-more-than-just-luck-181708">original article</a>.</p>