key: cord-0876099-7xqdv9o9
authors: Snedden, Celine E.; Makanani, Sara K.; Schwartz, Shawn T.; Gamble, Amandine; Blakey, Rachel V.; Borremans, Benny; Helman, Sarah K.; Espericueta, Luisa; Valencia, Alondra; Endo, Andrew; Alfaro, Michael E.; Lloyd-Smith, James O.
title: SARS-CoV-2: Cross-scale insights from ecology and evolution
date: 2021-03-26
journal: Trends Microbiol
DOI: 10.1016/j.tim.2021.03.013
sha: a298cfb4501adce52397a44eb60d0e0e1cdd22f5
doc_id: 876099
cord_uid: 7xqdv9o9

Ecological and evolutionary processes govern the fitness, propagation, and interactions of organisms through space and time, and viruses are no exception. While COVID-19 research has primarily emphasized virological, clinical, and epidemiological perspectives, crucial aspects of the pandemic are fundamentally ecological or evolutionary. Here, we highlight five conceptual domains of ecology and evolution – invasion, consumer-resource interactions, spatial ecology, diversity, and adaptation – that illuminate (sometimes unexpectedly) the emergence and spread of SARS-CoV-2. We describe the applications of these concepts across levels of biological organization and spatial scales, including within individual hosts, host populations, and multi-species communities. Together, these perspectives illustrate the integrative power of ecological and evolutionary ideas and highlight the benefits of interdisciplinary thinking for understanding emerging viruses.

in bats. The diversity of bat viruses, if paired with contact among humans and bats, potentially via intermediate hosts, can provide multiple opportunities for successful cross-species invasion to occur, as described by the propagule pressure hypothesis [15, 22, 23] . Several groups of batborne viruses, including the Henipaviruses and Ebolaviruses, are well-known to have caused numerous outbreaks via independent zoonotic transmissions [23] . Given evidence of multiple spillover events of SARS-like coronaviruses [24] , further investigation is warranted into whether SARS-CoV-2 could have been introduced to humans more than once. Once introduced, the contrast between the robust antiviral defenses in bats and humans, combined with the immunological naïveté of the human population, may have facilitated the successful invasion of SARS-CoV-2 as suggested by the enemy release hypothesis [17, 25] .

The population dynamics of a virus invariably depend on consumer-resource interactions, in which consumers rely on and directly impact resource availability. These interactions are a critical component of ecological community structure and provide the foundation for classical epidemiological models, where populations of infected hosts grow by "consuming" susceptible [38] . In such heterogeneous landscapes, synchronous dynamics, wherein populations rise and fall concurrently, increase the likelihood of population-wide extinction. Such synchrony can arise from correlated exogenous factors (e.g., climate conditions) and/or sufficient dispersal [39] . For viruses, if prevalence declines simultaneously in connected patches, the absence of highprevalence sources prevents dispersing hosts from recolonizing locally extinct patches [39, 40] .

Public health officials can leverage this principle to limit the spread of emerging infectious diseases if control policies are coordinated across cities and regions to promote synchronous declines in prevalence. Unfortunately, the lack of coordination plaguing the COVID-19 response has allowed re-seeding of outbreaks in locales that had previously contained SARS-CoV-2, leading to more cases and more interventions needed [5].

These spatial ecology concepts can also illuminate viral spread within the spatially-structured organs and tissues of an infected host. Because viral replication depends on many factors, including temperature, immune response, and cellular receptor and protease expression, different tissues act as sources or sinks [41] . For example, to enter a cell, the SARS-CoV-2 spike protein must bind the ACE2 receptor and be primed by the protease TMPRSS2, although other receptors and proteases may also be involved [42] . Tissues with sufficient co-expression of ACE2 and TMPRSS2 (e.g., nasal cavity) may act as sources that seed infection of surrounding areas with lower expression levels (e.g., bronchioles) [16, 43] . When ACE2 is expressed without TMPRSS2 (e.g., the heart), a tissue may function as an ecological trap, where virions bind target cells but cannot enter or replicate [3, 41, 43] . Interestingly, this concept can be leveraged to design therapeutics (e.g., [44] ). Physical transport mechanisms can also create ecological traps: for instance, SARS-CoV-2 may infect the central nervous system [19] , but the viral particles J o u r n a l P r e -p r o o f Journal Pre-proof produced in these tissues cannot readily transmit between hosts. Additionally, SARS-CoV-2 largely infects the human upper respiratory tract, from which produced virions are readily expired, whereas MERS-CoV and SARS-CoV infections predominantly reside in the lower respiratory tract, from which viral particles cannot readily transmit between hosts [45] . This difference in tissue tropism affects the transmissibility of these coronaviruses, and likely their pandemic potential. These examples demonstrate that models designed in spatial ecology can integrate knowledge from molecular biology (e.g., receptor affinity), multiomics (e.g., receptor expression), and physiology (e.g., tissue connectivity) to uncover patterns that underlie varying transmission characteristics and pathogenicity of different viruses.

Concepts and tools from spatial ecology allow us to identify and predict landscapes at high risk of experiencing cross-species spillover [46] . In particular, anthropogenic landscape changes increase spillover risk by: (i) altering the abundance and distribution of wildlife hosts, with highly modified areas potentially attracting a greater abundance of known reservoir hosts of zoonoses (e.g., rodents and some bat species), (ii) promoting stress-induced shedding and host susceptibility, and (iii) increasing contact rates among domestic animals, wildlife, and humans [1, 2, 11, 22, 47] . While interspecific contacts are difficult to quantify in the wild, advances in animal tracking [48] , data sharing platforms (e.g., Movebank), and quantitative methods [49] can refine our predictions of animal encounters, so additional monitoring can be directed to high-risk locations. However, given the difficulty of identifying and tracking the multitude of potential hosts, future applications of spatial ecology to understanding and preventing cross-species transmission may focus increasingly on resilience, rather than risk, within landscapes. Scientists have called for ecological countermeasures to prevent future pandemics, including fostering J o u r n a l P r e -p r o o f Journal Pre-proof landscape immunity. Interdisciplinary collaborations (from disease ecologists, conservation practitioners, immunologists, and many more) are necessary to understand and maintain landscape immunity across diverse ecosystems and to formulate clear guidance for policymakers [22] .

The evolution of organisms hinges on the accumulation of heritable mutations over successive generations, which can generate phenotypic variation. When studying virus evolution, it is essential to note that virus populations can be defined simultaneously at several nested scales (within their hosts, within host populations, and across host species communities). Evolutionary forces (e.g., mutation, selection) affect viral diversity and fitness concurrently at all of these scales, always mediated by the common currency of viral genomes. Due to the inherently intertwined nature of evolutionary processes at these different scales, we explore each concept first at the within-host scale, where viral factors (e.g., mutation rates) and host pressures (e.g., immune responses) act proximately to generate viral diversity and perhaps drive adaptation [2] .

Then, we discuss how processes functioning within host populations and across host species further shape the evolutionary trajectory of an emerging virus.

increases ACE2 binding affinity. E484K exhibits increased binding affinity to ACE2 and reduced neutralizing activity of monoclonal antibodies [71] .

In host populations, selection favors viral variants that can transmit between hosts and propagate through the population; thus, rising frequency of particular variants suggests a selective advantage. However, similar patterns could arise due to founder effects or stochasticity [72] , so cautious interpretation is warranted. For SARS-CoV-2, D614G rose to high frequency in separate global outbreaks and became dominant worldwide by March 2020 [68, 73] , and phylogenetic analysis in the United Kingdom suggests D614G approached fixation after introduction into a region dominated by the wild-type [73] . These findings are consistent with an adaptive role for D614G, which is further supported by evidence that it promotes increased transmissibility compared to wild-type: (i) more efficient transmission in hamsters, (ii) increased replication in the upper respiratory tract of humans and hamsters in vitro and in vivo, and (iii) the spike conformational mechanism described above [68, 69, 74, 75] . Similarly, B.1.1.7 became the dominant lineage in the United Kingdom within three months of its emergence in late September 2020, while B.1.351 and P.1 rose rapidly in frequency in South Africa and Brazil, respectively [59, 76] . Although these lineages appear to have emerged independently in different countries, they share several key substitutions in the spike protein (D614G, N501Y, E484K) associated At the scale of cross-species emergence, the role of virus adaptation is the subject of longstanding debate: when (if ever) is adaptation required, and where does it occur [78] ? Natural selection can drive the evolution of a trait that is later commandeered for a new function, and such exaptation of viruses in animal reservoirs can facilitate host jumps. Genetic analysis has revealed a furin recognition motif in the SARS-CoV-2 spike protein, which facilitates binding of human ACE2 and enables cleavage by the furin protease (Zhang et al. 2020). This motif is present in a coronavirus found in Malayan pangolins (Manis javanica) but is absent in the coronavirus (RaTG13) most genetically similar to SARS-CoV-2 (found in horseshoe bats;

Rhinolophus affinis) [6] . The acquisition of this motif (via an unclear pathway) may have functioned as an exaptation that mediated transfer of the SARS-CoV-2 progenitor from wildlife into humans. Since cellular entry is a key determinant of viral host range, the use of highly conserved receptors (and hence a generalist life history) may function as an alternative type of exaptation that provides more opportunities for spillover events [80, 81] . For example, ACE2 is highly conserved among humans, various bat species, and potential intermediate hosts [23] .

Indeed, many host species have proved susceptible to SARS-CoV-2, including ferrets and cats [82] ; in silico analysis identifies many other potentially susceptible species, providing insights 

• Foundational concepts from ecology and evolution can elucidate the emergence and spread of SARS-CoV-2, and all viruses, across multiple scales.

• Ecological and evolutionary methods that characterize population dynamics of organisms are potent tools to investigate viral growth and spread within individual hosts, or epidemic growth in host populations.

• The field of macroevolution classically studies the diversification and adaptation of multicellular organisms, but major opportunities exist to apply macroevolutionary concepts to the evolution of viruses.

• Concepts from spatial ecology, from source-sink dynamics to synchrony, can help understand patterns and processes in the emergence of viruses. 

Origins of major human infectious diseases

Emerging infectious disease: what are the relative roles of ecology and evolution?

Gradient in the Respiratory Tract

Exotic plant invasions and the enemy release hypothesis

Microbial dose response modeling: past, present, and future

Neurological Complications Associated with the Blood-Brain Barrier Damage Induced by the Inflammatory Response During SARS-CoV-2 Infection

Modeling rabbit responses to single and multiple aerosol exposures of bacillus anthracis spores

Invasion dynamics in spatially heterogeneous environments

Land use-induced spillover: a call to action to safeguard environmental, animal, and human health

Bat-borne virus diversity, spillover and emergence

Model-informed COVID-19 vaccine prioritization strategies by age and serostatus

Disentangling the dynamical underpinnings of differences in SARS-CoV-2 pathology using within-host ecological models

Modelling viral and immune system dynamics

Target cell limited and immune control models of HIV infection: a comparison

Ecology of zoonoses: natural and unnatural histories

Origins of the 2009 H1N1 influenza pandemic in swine in Mexico

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Transmission of SARS-CoV-2 on mink farms between humans and mink and back to humans

COVID-19 epidemic in China

Spatial synchrony in population dynamics

) Persistence, chaos and synchrony in ecology and epidemiology

Virus population extinction via ecological traps

Cell entry mechanisms of SARS-CoV-2

SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes

In vitro characterization of engineered red blood cells as viral traps against HIV-1 and SARS-CoV-2

Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics

The Ecology of Nipah Virus in Bangladesh: A Nexus of Land-Use Change and Opportunistic Feeding Behavior in Bats. Viruses 13, 169 data

Effect of host species on the distribution of mutational fitness effects for an RNA virus

Emerging SARS-CoV-2 mutation hot spots include a novel RNAdependent-RNA polymerase variant

Coronaviruses: an RNA proofreading machine regulates replication fidelity and diversity

The coronavirus proofreading exoribonuclease mediates extensive viral recombination

No evidence for increased transmissibility from recurrent mutations in SARS-CoV-2

Case Study: Prolonged Infectious SARS-CoV-2 Shedding from an Asymptomatic Immunocompromised Individual with

Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host

Matters of Size: Genetic Bottlenecks in Virus Infection and Their Potential Impact on Evolution

Evolving Insights from SARS-CoV-2 Genome from

Preliminary genomic characterisation of an emergent SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations. tool. , PANGO lineages

Genomic analysis of 15 human coronaviruses OC43 (hCoV-OC43s) circulating in France from 2001 to 2013 reveals a high intra-specific diversity with new recombinant genotypes

Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic

The evolutionary history of ACE2 usage within the coronavirus subgenus Sarbecovirus

Evolutionary insights into the ecology of coronaviruses

Multiple scales of selection influence the evolutionary emergence of novel pathogens

Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity

Mapping neutralizing and immunodominant sites on the SARS-CoV-2 spike receptor-binding domain by structure-guided high-resolution serology

Tracking changes in SARS-CoV-2 spike: evidence that D614G increases infectivity of the COVID-19 virus

Structural and functional analysis of the D614G SARS-CoV-2 spike protein variant

Increased Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7 to Antibody Neutralization

On the evolutionary epidemiology of SARS-CoV-2

Evaluating the effects of SARS-CoV-2 spike mutation D614G on transmissibility and pathogenicity

Spike mutation D614G alters SARS-CoV-2 fitness

SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and transmission in vivo

Resurgence of COVID-19 in Manaus, Brazil, despite high seroprevalence

SARS-CoV-2 B.1.1.7 escape from mRNA vaccine-elicited neutralizing antibodies

Identifying genetic markers of adaptation for surveillance of viral

Natural selection in the evolution of SARS-CoV-2 in bats created a generalist virus and highly capable human pathogen

Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus 2

The foot-and-mouth epidemic in Great Britain: pattern of spread and impact of interventions

Epidemic dynamics at the human-animal interface

Inferring infection hazard in wildlife populations by linking data across individual and population scales

Disease-structured N-mixture models: a practical guide to model disease dynamics using count data

Data integration for large-scale models of species distributions

An ecological framework for modeling the geography of disease transmission

Species distribution models are inappropriate for COVID-19. estimation of disease prevalence in multi-tissue disease systems

Accounting for imperfect detection reveals role of host traits in structuring viral diversity of a wild bat community

Iterative evolution of large-bodied hypercarnivory in canids benefits species but not clades

Species Selection: Theory and Data

Beyond Reproductive Isolation: Demographic Controls on the Speciation Process

The Red Queen and the Court Jester: Species Diversity and the Role of Biotic and Abiotic Factors Through Time

Virus taxonomy in the age of metagenomics

Viral Phylodynamics

• Can insights from invasion ecology be harnessed to formulate a new generation of mechanistic dose-response models? Can we leverage biomedical findings to model a viral exposure

• Does pre-existing immunity to SARS-CoV-2 arise from prior exposure to endemic coronaviruses? If so, do differences in these virus community interactions explain geographic variation in pandemic intensity? Can consumer-resource models be combined with patient data to investigate the impacts of pre-existing immunity on disease course?

• Can animal tracking technologies reveal the interactions of potential reservoir and intermediate hosts of SARS-CoV-2? Does overlaying this information with human population data reveal regions and species that may have been involved in SARS-CoV-2 spillover? Can these techniques identify high risk areas for future emerging viruses?

• How is SARS-CoV-2 tissue tropism influenced by features of the within-host landscape (e.g., temperature, pH, protein expression)? Can species distribution models incorporate this information to clarify the apparent disparities between ACE2 expression and SARS-CoV-2 tissue tropism?

We thank all participants of the seminar where the ideas for this manuscript were formulated. We apologize to the many authors whose work we were unable to include because of space