The pathway of the SARS-CoV-2 originating in nature, leading to a pandemic can be viewed as several preceding events and processes (see Fig. 1):
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1.
Origins of virus in the animal kingdom
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2.
Transmission to captive and domesticated animals
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3.
Interspecies transmission to humans
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4.
Local spread and epidemics in humans
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5.
Global spread towards a pandemic
Origins of the virus in the animal kingdom
A large number of emerging infections in humans originate from animals. Examples include HIV, SARS, Ebola and other infections. Of these a wide range of diseases are caused by the RNA family of coronaviruses. Theories of its origins are debated. Studies using molecular clock dating analyses of coronaviruses found common ancestor around 10,000 years ago, while recent evolutionary models have placed its origins millions of years ago [6].
The enduring relationship between bats, avian coronaviruses and their other hosts include co-divergence and co-evolution [7]. The SARS-CoV (that caused SARS) emerged from Chinese Rhinolophus affinis (horseshoe bats) from a milieu of several similar viruses that existed in this species of bats [8]. The corona viruses were also isolated from clinically normal wild animal species (e.g. Himalayan palm civets and raccoon dog) in wild animal markets in Shenzen, the People’s Republic of China [9]. Thus, reservoirs of the corona viruses are circulating among different species, some asymptomatic and a few causing symptomatic illness though bats form their main reservoir [10]. The novel SARS-CoV-2 is the seventh corona virus known to infect humans, emerged from this milieu and it is found in its natural host the bat Rhinolophus affinis or Manis javanica (Malayan pangolins) illegally imported into Guangdong province. Modeling and simulation studies indicate that “over two-thirds of SARS-CoV-2-like zoonotic events would be self-limited, dying out without igniting a pandemic” [11].
Transmission to domesticated animals
Transmission of corona viruses across species is well known. The recent report of the Joint WHO-China Study on the origins of COVID-19 found the most closely related forms of the virus in bats and pangolins [10]. However, they were not sufficiently similar to be the direct link suggesting the need to search for alternative reservoirs. Cats and mink are highly susceptible to the virus and are considered potential reservoirs.
The new host could act as conduits of transmission rather than as reservoirs. Civets were favored as intermediate hosts in the previous epidemic of severe acute respiratory syndrome (SARS) and pangolins in the case of COVID-19. However, epidemiological studies in humans and similar tracing of infections in animals have failed to find an intermediate source.
Similar situations when new CoV strains emerged from mutation of existing strains or changed its virulence from existing strains have been observed in the past, e.g. the emergence of a new group I porcine CoV responsible for the porcine epidemic diarrhoea CoV (PEDV) in 1970s and 1980s [12]. A corona virus in bats, which was non-pathogenic to bats was implicated in causing fatal diarrhoea in swines [13]. They also jumped species to infect farm animals (e.g. turkey and chicken) and domestic pests such as rodents [14,15,16]. Other species affected by novel mammalian coronaviruses include camels, bats, mice, dogs, and cats [17]. The resultant illness of often mild to severe with enteric or respiratory symptoms or a more systemic febrile illness.
Although there are a few reports of SARS-Cov-2 transmission from humans to animals there is little evidence that domestic animals are an important reservoir of SARS-Cov-2 virus. A comprehensive understanding of the virus spread from human to animal and vise versa is crucial for its control and prevention of future similar events. As such, this pathway is included when developing the generic conceptual model.
Transmission to humans
The ability of the Covid-19 to spread is its mechanism of replication and mutation, common to many RNA viruses [18]. RNA viruses have high rates of error during replication due to substitutions, insertions and deletions [19]. This makes it an excellent candidate for rapid host switching, and the emergence of variants that could have properties of higher transmissibility or pathogenicity. The mutation that enabled a species jump is likely to be localized in its ability to invade the cells of another animal species or humans. Evidence supports the view that ancestors of SARS-CoV in bats developed the capacity to enter human cells only after it mutated to produce a viral glycoprotein that binds to angiotensin converting enzyme 2 (ACE2) receptors on cell surfaces [20].
Increasing contact between animals and humans augments the risks of inter-species transmission from wild or domestic animals to humans, and there are three such situations: extension of human settlements closer to forests, wet markets and animal husbandry.
Extension of human settlements
At the global level, the extents of deforestation is a proxy measure of extension of human settlements. From 1990 to 2015, the global forest cover has reduced from 31.6% of the earth’s land surface area to 30.6% [21]. Almost 50% of this is due to farming, grazing of livestock, mining for metals, gas and fossil fuels. These, especially the former two activities promote interactions between wild animals and domesticated animals and thereby humans. The reasons and rates of deforestation vary: in Malaysia and Indonesia its due to plantations for palm oil and in the Amazon, it’s for cattle ranches, farms, and soya plantations [22]. In addition, in Asia and Africa expanding population and limited land has led to human settlements within and near to forests, progressively forcing wild animals into closer contact with humans and domesticated animals.
Wet markets
In wet markets, different live species (vertebrates and invertebrates) are caged close to each other in busy urban settings. China wet markets are implicated in the Covid-19 and are now considered an important source of its spread across species and to domestic animals and humans [23]. The presence of wet markets in China, Vietnam and Taiwan is a cultural preference of ‘freshness’ as an important aspect of culinary appreciation. The environment and appearance of wet markets (liberal use of water and wetness) give a sense of freshness which is resonant with their culinary culture. This is reinforced by the ambiance, the sensory cues such as free use of water and wetness, and trust created by vendors to provide fresh food. Wet markets were a source of H5N1 avian influenza in humans and probably the current Covid-19 pandemic.
Animal husbandry
Factory farms contain large population of domesticated animals which form an important reservoir for any potential infections. Though yet to be recognized as a major factor in COVID-19, there is evidence of human spread from farmed minks (Neovison vison) in the Netherlands [24]. Surveillance data showed large transmission clusters of SARS-CoV-2 with increased mortality in minks and subsequent evidence of SARS-CoV-2 infection with an animal sequence signature in 68% of farm residents, and employees. This led to culling of millions of minks in Netherlands and Denmark, similar to what was done in Europe during the epidemics of 2009 (H1N1) pandemics when billions of farm animals were destroyed.
Local spread and epidemics
The situation to generate an outbreak is achieved when human-to-human transmission becomes possible and a critical mass of humans are infected. The local spread begins to propagate when the basic average reproductive number exceeds unity [25]. More detailed analyses have shown the importance of super-spreading events in generating the epidemic [26]. There is evidence of the presence of multiple small epidemics in cities prior to the eruption of a major epidemic [27] Genome sequencing from Washington state indicates that there was cryptic transmission of the COVID-19 from a single source as early as January 2020.
Overcrowding promotes the spread of epidemics through aerosols, droplets and fomites and studies from China show that the epidemics have larger total attack rates and last longer than less dense and less populated cities [28]. Population pressures have exacerbated the process of urbanization and the congestion within cities. Key determinants of congested cities are rapid urbanization coupled with an increasing population. The current global population of 7.8 billion is the highest ever number of human inhabitants in the planet and it continues to increase. Increased human mobility within cities and countries are other factors promoting epidemics and the interventions restricting mobility are well known to control the spread of the disease [29]. There is research to show that connectivity within cities is likely more important for the the spread of COVID-19 than population density [30].
Unplanned urban developments with its combination of overcrowding, poor levels of personal hygiene due to scarcities in amenities such as running water, inadequate sanitation, confined poorly ventilated houses, production of solid waste and high air pollution are all likely to accelerate the spread of COVID-19 and other similar respiratory diseases within and across households. The detection of the COVID-19 RNA in solid waste feces suggest another potential pathway of spread of the virus in urban and peri-urban areas [31].
On the other hand, non-communicable diseases that are linked to unhealthy diets and lifestyles are main consequences of urbanization. These are associated with more severe illness and higher mortality with Covid-19.
Global spread towards a pandemic
Global spread is mainly due on international travel, especially during the incubation period [32]. In recent times humans have become increasingly mobile and travel to almost all parts of the planet. It is estimated that 4.5 billion passengers were carried by airlines in 2019, giving an opportunity for rapid and wide spread of infections and to generate pandemics [33].
In the case of COVID-19 the major spread has been infected humans who travelled to different locations of the globe as tourists or for work. Human species are mobile in relation to individual distance covered as well as frequency of movement. The persistence of the virus on plastic and metal surfaces, detection among baggage handlers in airports, spread within the cabins of airlines and cruise ships all indicate how its spread across borders was facilitated by non-human ‘artefacts’ [34].
Another factor is the possibility of particles in air pollution and dust storms acting as careers of viruses or worsening the severity of illness, thereby promoting virus excretion and its spread [35].
The direct role of climate change on generating the COVID-19 local epidemics is less well known. In the case of influenza, a warming climate, the rapid weather variability intensifies the epidemic risk that may increase even by 50% in some northern mid-latitude regions [36]. Researchers in China found that mean ambient temperature had an impact in low temperature (below a mean of 30 C) [37]. This could be partly a direct effect of ambient temperature (and humidity in the case of influenza) on survival of the virus in the environment or indirect effects that lead to changes in human behaviours, e.g. use of heaters or air conditioners during warmer weather which increases circulation of air within a confined space.
Climate change undoubtedly exert pressure on wildlife through which it initiates the various indirect mechanisms paving way to extinction. A healthy eco-system with biodiversity could contain viruses and prevent them from jumping to new host species from the wild. Viruses emerge and fade without much damage to its wild hosts in undisrupted, diverse eco-systems which are well separated from human inhabitants. Thousands of mammalian viruses may exist potentially harmful to humans and domesticated animals. Urgent actions leading to biodiversity protection are imperative for prevention of climate change as well as the next pandemic. It is well documented that almost half of zoonoses emerged after 1940 could be traced to disrupted biodiversity [38].
Though yet to be recognized as a major factor in COVID-19.
Domesticated animals are fertile grounds for potential global epidemics [39]. The large-scale outbreaks of SARS-CoV-2 in mink farms were initially reported from Denmark and Netherlands [24], followed by other parts of Europe, Canada and the United States leading to a de facto shutdown of the mink industry in these countries [40].
There is yet no evidence of large scale human COVID-19 epidemics traced to factory farming, transmission by ingesting infected materials or animal husbandry. However, whole-genome sequencing confirmed mink-to-human transmission of SARS-CoV-2 in clusters of employees and their contacts in mink farms in Netherlands [24]. Further investigations also indicated unique mutations in SARS-CoV-2 variants, existence of multiple generations of the virus as well as a faster evolutionary rate of the virus in minks, leading to concerns on effectiveness of the current vaccines.
These outbreaks are of grave concern because of the magnitude of global factory farming industry. An estimated 70 billion animals are bred in farms for human consumption and factory farms house millions of poultry, pigs, cattle and other animals in constrained and controlled environments. If these animals and their meat products act as vectors, the infection could potentially spread locally as well as globally [41]. In the past several such epidemics have been reported, and examples include, Bovine Spongiform Encephalopathy caused by prions and spread by infected beef products that have nerve tissues, salmonella through chicken eggs, and Middle East Respiratory Syndrome (MERS) through direct or indirect contact with infected dromedary camels [42].