SARS-CoV-2 and COVID-19 –
Introduction
In late December 2019, a cluster of pneumonia cases were noted by the Wuhan Municipal Health Commission. Several of the initial patients had visited a large seafood and live animal market located in the centre of Wuhan, Hubei Province. [1,2] Samples from seven patients admitted at the start of the outbreak were analysed by the Wuhan Institute of Virology and found to be PCR-positive for coronavirus RNA, therefore providing evidence of a novel coronavirus outbreak. [3] The full genome sequence was shared by the Chinese authorities on the 11th of January 2020. [4] On the 30th of January, the World Health Organisation (WHO) first issued an alert that declared the outbreak in Hubei Province constituted a Public Health Emergency of International Concern, [5] and the official name “severe acute respiratory syndrome coronavirus 2” (SARS CoV 2) was adopted by the International Committee of Taxonomy of Viruses (ICTV) on the 11th of February. [6] SARS-CoV-2 causes coronavirus disease 2019 (COVID-19) and as of the 17th of November 2021, there has been over 254 million cases and 5 million deaths worldwide. [7] COVID-19 has changed life for everyone and has created a world that would have been unimaginable five years ago. The psychosocial implications of this pandemic are only just being released and will leave an imprint on those who lived through it.
Epidemiology
In 2003, studies showed that wild animals sold as food in Guangdong markets were carrying SARS coronavirus (SARS-CoV-1) and phylogenetic analysis indicated that the virus originated in bats and spread to humans via animals held in markets. [8] All coronaviruses known to infect humans are zoonotic, prone to cross-species transmission and can quickly adapt to new hosts. These properties are due to their large genome size; they have the largest known RNA genome which is non-segmented. [9]
Many early cases of SARS CoV 2 were linked to the Wuhan Nanhua Seafood market which provided initial evidence that this was outbreak of a novel coronavirus with zoonotic transmission. [1] However, in January 2020, evidence was being published of familial clusters of pneumonia associated with SARS CoV 2 indicating multiple examples of human-human transmission. [10,11] At this stage, it was being realised that asymptomatic infection is possible, and like SARS-CoV-1, human-human transmission was efficient and super-spreading events could lead to major outbreaks in hotels and hospitals. [10] All the elements required to cause a pandemic were in place – SARS-CoV-2 has relatively high infectivity, long incubation and shedding periods, as well as not requiring skin to skin contact to spread. [12,13]
Presently, there are many studies confirming the transmission of SARS-CoV-2 to be through respiratory droplets as well as aerosol, direct contact with fomites, and faecal-oral transmission. [14,15] This is to be predicted as the viral receptor is human angiotensin-converting enzyme 2 (hACE2) which is expressed in cells in multiple organ systems, such as lung alveolar and gastrointestinal cells. The non-human equivalent of hACE2 is abundant on cells of other species, meaning that coronaviruses present in other mammalian species may be pre-adapted to infect humans. [16]
Othman et al. investigated the effect of eight ACE2 variants to identify polymorphisms that may increase or decrease virulence in the host. There are quite a few discussions in the literature whether these genetic differences could explain the variation in presentation and outcomes in covid-19 patients, but their findings indicated that these changes in hACE2 would only have a minor effect on affinity. As a result, it is unlikely that any virus resistance related to the ACE2 gene exists. [17,18] Supporting this, Xue et al. looked at the population frequency of 388 missense variants and their affinity to the SARS-CoV-2 spike protein and found no obvious trend of changes in affinity and stability. [19] However, Suryamohan et al. found natural ACE2 variants where protective variants (K31R and E37K) showed decreased binding to S-protein, and K26R and T92I variants showed increased affinity when compared to wildtype ACE2. [20] The current research therefore shows potential varying susceptibility with polymorphic hACE2, but further research into the relationship between the virus, the peptidase function of ACE2, and angiotensin II levels in COVID-19 patients is needed.
Another area of current research is the faecal-oral transmission of SARS-CoV-2 which is more of a risk factor in developing countries. Current efforts in minimising the spread of COVID-19 assume that the virus is mostly transmitted from infected people by respiratory droplets produced while coughing and sneezing, as well as through direct contact with contaminated people and surfaces. [21] As SARS-CoV-2 is shed through the faeces of infected people, it can be introduced into public waterways as untreated wastewater and sewage. Transmission may also occur through inhalation of contaminated aerosols and droplets from wastewater plumbing systems, particularly in densely populated residential areas. [22] These alternative routes may explain the speed of the global spread of COVID-19.
A further alternative route is maternal-foetal transmission (vertical infection), and it is important to determine under what circumstances this can occur. Intrauterine transplacental transmission of viruses has been observed in prior outbreaks of emerging viral infections such as HIV, Ebola, hepatitis E, and Zika. Yet, in past epidemics of RNA viruses in the Orthocoronaviridae family, this method of transmission has either not been observed or is extremely rare. Breaking this pattern, reports of neonates testing positive for COVID-19 shortly after birth has brought into question whether vertical infection is possible. [23] Conversely, Di Toro et al. found no viral RNA in amniotic fluid, placenta, vaginal secretion and blood, suggesting that intrauterine/intrapartum transmission is unlikely. [24] Once again, more investigation is necessary as there is not conclusive evidence to confirm whether vertical infection is occurring, as well as its frequency in the community.
Discussed above is symptomatic spread of SARS-CoV-19 but the biggest challenge to preventing infection, lowering the R number, and epidemiology as a whole is asymptomatic transmission. A positive test result is the only condition for a COVID-19 case, which is unusual – normally, a test is used to confirm a clinical diagnosis, now it replaces it. Muddying the waters further is the fact that we do not know if said positive test result is paucisymptomatic, presymptomatic, or post-infection. [25] It is also not known with certainty to what extent patients without symptoms spread the virus. Because it needs extensive prospective clinical sampling and symptom screening from a representative sample of persons with and without illness, quantifying the percentage of people with asymptomatic infection is challenging. [26] A number of studies have been conducted to estimate this number and according to one meta-analysis, around one in four remain asymptomatic throughout the course of infection. [27] However, the study conducted by He et al. had a larger sample size and they found the pooled proportion of asymptomatic infection to be 15.6%. This means that it is virtually impossible to quarantine everyone infected without mass testing – something that is too expensive for countries with fewer resources. In order to aid real-world decision making, more research is needed to comprehensively understand asymptomatic COVID-19 infection.
Genomics and phylogeny
As touched upon earlier in this review, COVID-19 shares many features of previous coronavirus outbreaks (first cases linked to a wet market, zoonotic origin, spread via respiratory droplets), and this is reflected in its genomics. SARS-CoV-2 has a genome sequence similarity of 79% with SARS-CoV-1, and 50% with MERS-CoV-24, as well as having a genome which is similarly organised to other betacoronaviruses. The six functional open reading frames (ORFs), as shown in figure 1, are positioned from 5′ to 3′ in the following order: replicase (ORF1a/ORF1b), spike (S), envelope (E), membrane (M), and nucleocapsid (N). There are also seven potential ORFs encoding accessory proteins scattered among the structural genes. [28] The proteins which are encoded by these genes have a similar amino acid length to SARS-CoV-1 and these two viruses also share more than 90% amino acid identity for the structural genes. The non-structural proteins (NSPs) (which are elements of the replication and transcription complex (RTC) and also play a part in immune system evasion) are located in the first open reading frame [16]
Numerous studies have been published analysing the genetic data of SARS-CoV-2. This provides a wealth of information about the distinct lineages and substrains circulating in different geographic areas. This knowledge can be used to trace the routes of transmission from city to city, and country to country. The first Brazilian was infected during travel to Italy on February 25, 2020, and the network algorithm reflects this with a mutational link between an Italian and his Brazilian viral genome. [29] As well as retrospective information, this data can help us plan for the future. Full-genome analyses of SARS-CoV-2 may reveal new variants that change spike affinity with the ACE2 receptor, TMPRSS2 protease activity, and epitope mapping, which may help inform decisions made by public health authorities. [30] As the pandemic carries on with daily cases in the UK still around 40,000 [31], there is still a high chance of this virus mutating so much that it impacts vaccine efficacy. [32]
However, research is showing that these properties are not just features of SARS-Cov-2 -pathogenic variability may be a characteristic of animal coronaviruses as a whole. [33] The fact that all three newly emerging human coronaviruses (the agents of SARS, MERS, and COVID-19) cause significant morbidity and mortality in humans shows that zoonotic coronaviruses may be inherently pathogenic. Preliminary studies show that SARS-CoV-2 may trigger an inappropriate innate immune response characterised by reduced expression of interferons I and III and increased production of inflammatory cytokines, which is compatible with preliminary COVID-19 findings. [34]
Clinical features and pathogenicity
The presentation of COVID-19 is variable and ranges from mild symptoms to severe illness
Viral pneumonia, with fever and cough being the most prevalent for adults. [35] Other common symptoms include chills, muscle pain, sore throat, loss of taste and sense of smell, and breathing difficulties but people infected with the same variant of SARS-CoV-19 may have different symptoms, and their symptoms can change over time. There are three typical clusters of symptoms: one respiratory symptom cluster with cough, sputum, shortness of breath, and fever; one musculoskeletal symptom cluster with muscle and joint pain, headache, and exhaustion; and one digestive symptom cluster with stomach discomfort, vomiting, and diarrhoea. [36] These groups are then being used by researchers as predictors for “long covid” – persistent symptoms in patients after apparent resolution of infection, as well as predicting who will need hospitalisation. Huang et al. found that positive predictors during days 0 to 10 of infection include asymptomatic presentation, heart palpitations, and chronic rhinitis. [37]
Severe symptoms include tightness of chest and dyspnoea which can then progress to acute respiratory distress syndrome (ARDS), septic shock, metabolic acidosis and coagulopathy. [38] In a report looking at over 70,000 cases in China, symptoms appear after a 3–5-day incubation period and of those infected, 80% of cases were mild, 14% severe, 5% required intensive care. [39] There is ample research showing the genomic determinants of pathogenicity in SARS-CoV-2 correlating with severe disease and a high fatality rate. Gussow et al. looked at genomic features that differentiate SARS-CoV-2, SARS-CoV-1 and MERS from less pathogenic coronaviruses such as the nuclear localisation signals (NLSs) and inserts in the spike glycoprotein. Interestingly, gradual changes in the NLS in the nucleocapsids do not reflect a single mutation in the common ancestor but a convergent trend in the evolution of these viruses. [40]