pre-symptomatic viral transmission , which posed a major hurdle in halting the spread of the virus .
Another behavioral quirk of SARS-CoV-2 is how quickly it has changed . Researchers anticipated that the virus would mutate . They knew that new SARS-CoV-2 variants would emerge eventually . What blindsided them was the extent to which some of the viral mutants could dodge antibody defenses .
Another baffling observation was that some mutations were arising in geographically remote parts of the world . The virus , the researchers realized , was developing natural evolutionary workarounds against host immune defenses .
In the early months of the pandemic , the assumption — and hope — was that SARS-CoV-2 would not change too fast because , unlike most of its fellow RNA viruses , it has a “ proofreading ” protein whose job is to prevent too many changes to the viral genome .
But the virus did change , and researchers worry that if vaccine rollout remains sluggish , the viral changes may outpace our ability to keep up with them .
Know thine enemy
A microbe has only one goal — to survive and propagate . To achieve this , a virus must change in response to its environment . These adaptive changes occur through mutation . Mutations are a normal part of the life cycle of a virus and happen every time a virus makes copies of itself .
Some mutations are of no consequence , others can harm the virus itself , and still others can become advantageous to the microbe , allowing it to propagate more easily from host to host or to dodge the host ’ s immune defenses . If a mutation gives a virus an evolutionary advantage , this fitter variant can gradually outcompete others and become the dominant one .
On a basic level , to survive long-term , any organism must engage in a delicate balancing act between safeguarding its genome against too many mutations and introducing new adaptive mutations that render it better adapted to survive in its environment .
“ The whole viral evolution story has been puzzling ,” Knipe says . “ We thought initially the virus was pretty stable genetically , but the variants with the same multiple changes have arisen in several geographic areas . This not a gradual evolution .”
Rather , Knipe adds , recent studies suggest that viral recombination — or shuffling of segments of the viral RNA — may lead to new , more infectious genetic combinations of mutations .
In the case of SARS-CoV-2 , most mutations emerge simply as a consequence of adapting to a new host . Best current evidence suggests that SARS-CoV-2 made its way into people from bats , a transition that compels the virus to get better and better at invading the cells of its new host .
Other mutations to SARS-CoV-2 appear to arise in response to pressure from the host ’ s immune system . To ensure its survival inside the human host , the virus comes up with workarounds — escape mutations — that allow it to dodge immune defenses .
The most common , and best understood , immune defense is neutralizing antibodies , immune proteins that block the virus from entering and infecting cells . To prevent SARS-CoV-2 from entering human cells , antibodies latch onto an area of the virus called the receptor-binding domain ( RBD ). Logic would dictate that the virus would first develop escape-enabling mutations in this vulnerable part of its structure but , to the researchers ’ surprise , mutations are now appearing on other parts of the virus as well .
“ The virus is not changing only where the antibodies attack ,” Knipe says . “ It ’ s changing throughout the genome . Why is it changing so much all the way through ?” The question is also a clue . This observation raises an interesting hypothesis . It suggests that the virus may be experiencing immune pressure elsewhere on its genome and that such pressure does not arise from the antibody response . This indicates that antibodies are not the only troops deployed by our immune system to disable the enemy , Knipe said .
The emergence of viral variants that appear to be more transmissible points to the ability of the virus to shapeshift rapidly in response to immune pressure . This , in turn , highlights the importance of immunizing large swaths of the population , thereby reducing the number of hosts for the virus to infect and the number of opportunities to mutate .
Understanding viral behavior mandates aggressive genomic surveillance of SARS-CoV-2 but , just as importantly , research into how coronaviruses , in general , and other viruses replicate , Knipe said . The information derived from studying viral behavior , he added , can help scientists guess the pathogen ’ s next moves , such as the appearance of novel mutations , and factor them into the design of broadly acting therapies and vaccines that target multiple sites of vulnerability on the virus .
Lines of defense
Traditionally , scientists who study infectious diseases have paid more attention to the pathogen than the host . But COVID-19 , perhaps more so than other infectious diseases , has pointed to the importance of host-specific factors .
“ What ’ s really amazing with this particular infection is the crazy battle between the host and the pathogen ,” Alter says . “ It ’ s fascinating to see how the immune response can grab hold of this virus .”
Broadly , our defense against microbes arises from two branches of the immune system . Innate immunity comprises various protective mechanisms we are born with . Adaptive , or acquired , immunity is a form of continuing education for the immune system . As it encounters new pathogens , it learns how to deal with them .
Once the immune system meets a pathogen , it must recognize it as a foreign and retain a memory of it . Upon subsequent encounters , our immune defenses recognize the pathogen as a familiar foe and mount a rapid defense , often triggering minimal symptoms or no symptoms at all .
Broadly speaking , adaptive immunity uses two forms of defense : antibodies , the so-called humoral immunity , and T cells , also known as cellular immunity .
The role of the different types of immunity in COVID-19 has not been fully elucidated . Of the two arms , however , adaptive immunity has been the main focus of research efforts .
Does the dose make the poison ?
How the immune system responds early during infection could help scientists forecast disease trajectory and survival . The search for telltale clues — or biomarkers — to predict who will get severe disease and who will not is one of the more fundamental challenges right now .
One fairly straightforward predictor of disease severity is the amount of circulating virus in the blood , or the viral load . Research led by MassCPR member Jonathan Li compared viral