Module 1: Pathophysiology of COVID-19 and Evolving Efforts in 
Diagnosis, Treatment, and Prevention 
Virology and Immunology 
Updated: 19 May 2020 
 
Authors ​Bautista, Esther; Co, Luis; Lim, Nicole; Lukban, Gabriel; Manlutac, Emmanuel; Puno, 
Lorenzo; Roa, Miguel; Santos, Samantha; Simba, Arvin; Tapia, Angelo 
 
Consultant 
Ronald Allan Cruz, MSc 
 
 
This  module  discusses  the  pathophysiology  of  COVID-19  and  evolving  efforts  in  diagnosis, 
treatment,  and  prevention  of  the  disease.  Exploring  key  concepts  starts  with  the  nature  of 
the  SARS-CoV-2,  the  virus  causing  COVID-19  disease.  We  will  then  see  its  usual  clinical 
presentation,  and  how  the  proper  diagnosis  is  followed.  Lastly,  we  will  deal  with 
management  and  treatment,  from  asymptomatic  individuals  to  severe  cases  in the ICU, and 
how  research,  clinical  studies,  and  investigatory  therapeutics  are  paving  the  way  to beat the 
pandemic.   

 
 

 
TABLE OF CONTENTS 
I. Virology and Immunology 
A. Introduction 
B. Classification 
1. Genome 
2. Structure 
C. Pathogenesis 
1. Viral Entry 
2. Transmission Dynamics 
3. Immune Responses 
II. Clinical Presentation 
A. Signs and Symptoms 
1. Risk Stratification 
B. Diagnostics 
1. Molecular Assays 
2. Immunoassays 
3. Neutralization Assays 
C. Ancillary Studies 
1. Work-up for hospitalized patients 
2. Laboratory diagnostics 
3. Imaging 
III. Management and Treatment 
A. Clinical Course 
1. Disease Classification and its associated risk factors 
2. Case Fatality Rate 
B. Current Triage by the government 
C. Treatment 
1. Mild to Moderate Symptoms 
2. Severe Symptoms 
3. In Pregnant Patients 
IV. Developing Therapeutics 
A. Investigational Therapeutics 
B. Passive Antibody Transfer 
C. Vaccine Development 
V. Discussion Points and Review Questions 
VI. Module Summary 
 
 
 
 
 
 
 
 
 

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VIROLOGY AND IMMUNOLOGY 

Introduction 
Viruses  infect  all  cellular  life  forms,  some  of  which  are  responsible  for  a  variety  of 
human  infections  (e.g.  Rabies,  Dengue,  Influenza).  They  are  ​acellular  microscopic  parasites 
that  deliver  their  genome  into  a  host  cell  where  it  can  replicate.  Viral  genomes  may  be 
composed  of  genetic  material  with  different  configurations:  Double-stranded  DNA, 
single-stranded DNA, double-stranded RNA, or single-stranded RNA. The genome is enclosed 
in  a  protein  coat  known  as  a  ​capsid​.  The  genome,  capsid,  and  other  parts  of  the  genome  (if 
any)  constitute  what  is called a ​virion​, or virus particles. By inserting their genome into a host 
cell,  a  virus  can  repurpose  host  cell  proteins  to  replicate  their  genome  and  produce  more 
virions to spread to other hosts (Carter and Saunders, 2007). 
 
Human  coronaviruses  primarily  infect  the respiratory tract. Two well-known examples 
of  pathogenic  coronaviruses  are Severe Acute Respiratory Syndrome (SARS-CoV)  and Middle 
East  Respiratory  Syndrome  (MERS-CoV).  Both  originated  from  bats,  and  can  be  transmitted 
directly  to  humans  from  civets  and  dromedary  camels,  respectively.  On  the  other  hand,  the 
origin  of  SARS-CoV-2,  the  virus  that  causes  COVID-19,  is  still  being  determined.  Some  of  the 
most  prominent  signs  and  symptoms  of  patients  afflicted  with  COVID-19  include  ​fever,  ​dry 
cough​,  ​labored  breathing​,  and  ​bilateral  lung  fluids  ​on  imaging​.  Those  who  are considered 
to  be  mildly  affected  may  have  symptoms  such  as  dry  cough,  sore  throat,  and  fever.  This  is 
the  case  for  most  of  those  infected.  However,  some  patients,  particularly  the  elderly  with 
existing  comorbidities  such  as  cardiovascular,  cerebrovascular,  endocrine,  digestive,  and 
respiratory  diseases,  tend  to  develop  more  severe  symptoms  such  as  severe  pneumonia, 
pulmonary  oedema,  Acute  Respiratory  Distress  Syndrome  (ARDS),  or  multiple  organ  failure. 
(Chen ​et al.​, 2020).   
 
Wuhan  City  has  a  population  of  over  11  million,  making  it  the  most  heavily populated 
city  in  Central  China.  Last  December  2019,  a  kind  of  pneumonia  of  unknown  etiology  broke 
out.  Early  on,  clusters  of  patients  were  all  associated  with  the  local  Huanan  Seafood 
Wholesale  Market,  known  to  be  involved  in  the  trade  of  live  animals  such  as  poultry,  bats, 
marmots,  and  snakes.  The  Chinese  Centre  for  Disease  Control  and  Prevention  (CCDC) 
identified  the  causative  agent  to be the ​Severe Acute Respiratory Syndrome Coronavirus 2 
(SARS-CoV-2)​.  This  disease  would  then  be  named  ​COVID-19  by  the  World  Health 
Organization (WHO) (Sohrabi ​et al., ​2020).  
 
On  January  30,  2020,  WHO  declared  the  COVID-19  outbreak  to  be  a  Public  Health 
Emergency  of  International  Concern  (PHEIC).  Then,  on  March  11, 2020, WHO director general 
Dr.  Tedros  Adhanom  Ghebreyesus  declared  COVID-19  as  a  pandemic.  This  pandemic 
threatens  all  countries,  particularly  those  with  deficient  health  systems.  Globally,  there have 
been  ​4,542,347  confirmed  COVID-19  cases  with  ​307,666  deaths  as  of  ​May  16,  2020  ​11:15AM 
PST  (WHO,  2020). In the ​Philippines​, there have been ​12,305 confirmed COVID-19 cases with 
817  deaths  as  of  ​May  16,  2020  04:00PM  PST.  This  number  continues  to  rise  as  more 
individuals are tested (DOH-PH, 2020). 

Classification 

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Coronaviruses  are  classified  under  the  order  ​Nidovirales  and  are  further 
subclassified  into  four  genera:  ​Alphacoronavirus​,  ​Betacoronavirus,  ​Deltacoronavirus​,  and 
Gammacoronavirus​,  of  which  ​Alphacoronavirus  and  ​Betacoronavirus  are  known  to  infect 
humans  (See ​Figure 1.1 for the ICTV Classification of Coronaviruses). As a family, coronaviruses 
include  several  notable  human  coronaviruses  (HCoV)  that  cause  the  “common  cold”  (e.g. 
HCoV-229E,  -NL63,  -OC43,  -HKU-1)  (Liberman  ​et  al.​,  2010).  Two  of  the  most  noteworthy 
coronaviruses  are  SARS-CoV  and  MERS-CoV.  They  are  Betacoronaviruses  responsible  for  the 
SARS  worldwide  outbreak  in  2002-2003  with  8,096  cases  and  774  deaths  reported,  and  the 
MERS  outbreak  in  2012  with  2,102  cases  and  780  deaths  reported,  respectively  (Zhou  ​et  al​., 
2020, Zhu​ et al​., 2020).  

Figure 1.1.​ ICTV Classification of Coronaviridae Family of Viruses. From Pillaiyar et al., 2020. 

Genome 
Coronaviruses  have  the  largest  genome  of  all  RNA  viruses  that  infect  humans.  They 
consist  of  a  ​positive-sense,  single-stranded enveloped RNA with ​helical capsids that infect 
a  ​wide  range  of  hosts  aside  from  humans  such  as  bats,  other  mammals,  and  birds  (See 
Figure  1.2  for  COVID-19  genome).  The  genome  is  roughly  30  kb  in  size  and  is  5’-capped  and 
3’-polyadenylated. It is non-segmented, with up to 14 open reading frames (Zhu ​et al.​, 2020).  
  

Figure 1.2.​ Coronavirus Genome and Encoded Proteins. From Collier, Oxford, Kellam, Human 
Virology, 2016. 

Bats  appear  to  serve  as  a  natural  reservoir  for  a  majority  of  the  new  coronaviruses, 
with  other  animals  believed  to  be intermediate hosts such as the civet cat for SARS-CoV, and 
the  dromedary  camel  for  MERS-CoV  (Guan  ​et  al.​,  2003,  Chu  et  al,  2014).  COVID-19  viruses 
isolated  globally  share  a  79.6%  genetic sequence similarity to the SARS-CoV isolates from the 
SARS  outbreak  in  2003  (See  ​Figure  1.3  for COVID-19 relatedness with SARS-CoV isolates). The 
closest  known  relative  to  COVID-19  was  isolated  from  ​bats​,  with  a  ​96%  sequence  identity 

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(Zhou  ​et  al.​,  2020).  Given  the  low  amount  of  interaction  between  bats  and  humans,  it  is 
believed  that  an  intermediate  host  was  also  involved  in  the  transmission  of  COVID-19.  The 
pangolin  has  been  implicated  as  a  potential  intermediate  host  due  to  the  high  levels  of 
similarity  between  pangolin  coronaviruses  and  COVID-19  (Lam  ​et  al.​,  2020).  Other  market 
animals  such  as  civets  or  pigs  may  also  be  potential  intermediate  hosts  between  bats  and 
humans, and further study is required (Lu e ​ t al.​, 2020). 

Figure 1.3​. Relatedness of “SARS-like” Betacoronaviruses to Select SARS-CoV-2 (COVID-19) 

samples isolated from China, USA, and Japan.  

Structure 
The  name  “Coronavirus”  comes  from  the  Latin  word  “corona”  meaning  “crown”, 
denoting  the  crown-like  appearance  of  its  virions.  Coronaviruses  contain  four  major 
structural  proteins:  Spike  (S),  Membrane  (M),  Envelope  (E),  and  the  Nucleocapsid  (N)  protein 
(See F
​ igure 1.4​ for COVID-19 structural proteins) . 

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Figure 1.4​. Major Structural Proteins of the Coronavirus. From AMBOSS. 

 
The  N  proteins  bind  with  the  RNA  genome  to  make  the  helical  ribonucleoprotein 
(RNP),  which  is  packaged  within  the  viral  envelope. The M protein is the most abundant, and 
is a transmembrane glycoprotein that defines the shape of the viral envelope. The E protein is 
believed  to  play  a  critical  role  in  virus  infectivity.  The  S  protein  is  a  surface protein that binds 
to  host  cell  receptors  to  facilitate  entry,  and  is  also  the  binding  site  of  host antibodies (Millet 
and  Whittaker,  2015).  ​Genetic  polymorphisms  affecting the ​S protein in COVID-19 can cause 
lethal  human  diseases  such  as  SARS  and  MERS.  This  altered  genetic  structure  of S proteins 
can  be  activated  by  furin,  a  host  cell  enzyme  found  in human tissues such as the lungs, liver, 
and  small  intestines  (Andersen  et  al​.,  2020).  This  may  explain  the  heightened  risk  of  the 
elderly  with  comorbidities  due  to  the  expanded  cellular  tropism  of  COVID-19  S  proteins. 
SARS-CoV  and  other  related  coronaviruses  do  not  have  these  S  protein  polymorphisms  and 
therefore  do  not  have  furin  activation  sites,  which  may  explain  why  SARS-CoV  infections  in 
the human body are more localized as compared to COVID-19 (Walls​ et al.,​ 2020).  
  
Pathogenesis 
Viral Entry 
SARS-CoV-2  and  the  immune system’s reaction to the pathogen have the potential to 
inflict  severe  damage  in  the  lung  parenchyma  and  the  body  at  large.  Unsurprisingly,  the 
lungs  were  found  to  be  involved  in  crucial  steps  facilitating  entry  and  eventual  infection  of 
the  virus  in  the  body.  One  mechanism  by  which  the  virus  enters  the  respiratory  tract  is  via 
inhalation  of  droplets  containing  SARS-COV-2  through  the  mouth  or  nose,  making  its  way 
into the lower respiratory tract.  
 
In  the  lungs,  SARS-CoV-2  infects  epithelial  cells  containing  the 
angiotensin-converting-enzyme  2  ​(ACE2)  ​receptor​.  Given  that  ACE2  is  strongly  expressed 
on  the  outer  apical  membrane  of  well-differentiated  ciliated  epithelial  cells  ​(Jia  ​et  al.​,  2005) 
and  ​type  II  pneumocytes  on  lung  tissue,  these  cells  are  considered  the  most  susceptible to 
SARS-CoV-2  infection  in  the  lungs.  Type  II  pneumocytes  are  one  of  two  major  types  of  cells 
found  in  alveoli,  the  site  of  gas  exchange  in  the  lungs.  These  pneumocytes  function  to 
produce  and  secrete  surfactant  to  reduce  surface  tension  and  prevent atelectasis or alveolar 
collapse.  The  ACE2  receptor  is  a  component  of  the  renin-angiotensin-aldosterone  system 
(RAAS),  which  serves  to  regulate  plasma  volume  and  blood  pressure.  The  common  form  of 
ACE  we  know  of  activates  the  more  potent  angiotensin  II  by  cleaving  angiotensin  I. 
Conversely,  ACE2  plays  a  regulatory  role  by  facilitating  a  decrease  in  angiotensin  II  levels, 
leading  to  an  increase  in  angiotensin  (1-7).  By  this  mechanism,  an  increase  in  vasodilatory 
effects has been observed, opposing the vasoconstriction mediated by the RAAS pathway. 
 
The  full  mechanism  of  SARS-CoV-2  endocytosis  and  fusion  with the cell membrane is 
still  being  studied.  The  ​Spike  (S) glycoprotein found on the virus is crucial to the virus’ ability 
to ​adhere to ACE2 receptors. SARS-CoV-2 Spike or S-protein contains two subunits, namely S1 
and  S2  (refer  to  ​Figure  1.5​).  S1  was  found  to  determine  cellular  tropism  and  the key receptor 
binding  domain  (accounting  for  the  ACE2  receptor-bearing cell tropism), while S2 is involved 
in  membrane  fusion  between  the  virus  and  the  target  cell  via  heptad  repeats  HR1  and  HR2 
(Guo  ​et  al.​,  2020)​.  TMPRSS2,  a membrane serine protease, primes the attached virus for entry 
by  cleaving  the  S-protein,  facilitating  endocytosis.  A  similar  mechanism  was  observed  in  the 

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pathogenesis  of  SARS-CoV,  but  SARS-CoV-2  binds  more  efficiently  to  the  ACE2  receptor 
making  it  more  readily  infectious  and  transmissible  ​(Song  ​et  al​.,  2018)​.  Risk  factors  that 
increase  susceptibility  of  the  host  to  infection  and  disease  progression  include  age  over  65 
years  and  comorbidities  such  as:  hypertension,  chronic  obstructive  pulmonary  disease, 
diabetes, and cardiovascular disease (​ Guo e ​ t al.​, 2020​). 
 

 
Figure 1.5​. Viral & Host factors involved in the pathogenesis of COVID-19. From ​Guo et al., 
2020. 
 
Once  inside  the  cell,  the  virion  releases  its  genetic  material  into  the  cytosol. 
Positive-sense  RNA,  like  mRNA,  is  a  ​template  for  protein  translation  using  inherent  host cell 
machinery.  The  SARS-CoV-2  genome  is  translated  into  viral  nonstructural  proteins  through 
the  cell’s  ribosomes,  resulting  in  the  formation  of  ​replication-transcription complexes ​(Guo 
et  al.​,  2020).   In  particular, the nonstructural proteins translated from the viral RNA are pp1a & 
pp1ab  ​(Guo  ​et  al​.,  2020).  These  replication-transcription  complexes  encode  the  viral  proteins 
necessary  to  ​sustain  viral  replication​.  From  here,  the  newly  replicated  viral  RNA  are 
packaged  into  new  virions  through  the  host  golgi  apparatus  and  are  prepared  for release to 
infect other cells. 
 

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The  finished  virions  are  exocytosed  into  the  bloodstream  possibly  causing  viremia 
(Lin  ​et  al.​,  2020)​.  These  infect  other  cells  in  the  body  containing  the  transmembrane  ACE2 
receptor,  such  as  in  the  heart,  kidneys,  gastrointestinal  tract, and endothelial cells of arteries. 
Its  presence  in  other  ACE2  containing  cells  is  evidenced  by  the  detection  of  SARS-CoV-2  in 
stool  samples,  as  intestinal  cells  are also found to express the same receptor. (Refer to ​Figure 
1.6​ ​for a summary of the mechanisms of viral entry and replication of SARS-CoV-2.) 
 

 
Figure 1.6​. Mechanism of Viral Entry and Replication of SARS-CoV-2. From The Economist. 
 
Transmission Dynamics 
SARS-CoV-2  is  posited  to  have  initially  infected  humans  through  zoonotic 
transmission  given  the  association  of  the  earliest  identified  cases  to  the  Huanan  Seafood 
Wholesale  Market.  This  is  evidenced  by  the  genomic  synonymy  (96.2%  similarity)  between 
SARS-CoV-2  and  a  SARS-like  coronavirus  found  to  infect  bats  called  ​bat  CoV  RaTG13  ​(Guo  ​et 
al.,  ​2020).  Other  mammalian  intermediate  hosts  such  as  civets  and  swine,  all  present  at  the 
wet  market  as  well,  are  suspected  to  be  part  of  the  transmission  chain,  increasing  the 
likelihood  of  the  exposure  of  SARS-CoV-2  to  humans, thus enabling the virus to readily cross 
the  species  barrier. Like what was mentioned in the earlier sections, scientists point to a likely 
intermediate  host  in  the  pangolin,  as  evidenced  by  a  99%  match  in  viral  genetic  sequences 
from animals and humans infected (Prompetchara e ​ t al., ​2020).  
 
The  most  common  modes  of  transmission  for  the  spread  of  SARS-CoV-2  are  through 
person-to-person  transmission  by  ​inhalation  and  other  means  of  ​exposure  to  droplets 
from  infected  individuals.  SARS-CoV-2  droplets  are  mainly  large  (>60  microns)  and  can 
spread  up  to  1  meter  upon  sneezing,  talking,  or  coughing.  ​Aerosolization  yields  a  ​3-hour 
viability ​period for the virus, important in infectious disease control protocol (Van Doremalen 
et  al.,  ​2020).  Viability  also  varies  on  different  surfaces,  lasting  longest  on  plastic  and stainless 
steel  at  72  hours, in contrast to copper (4 hours) and cardboard (24 hours) (Van Doremalen ​et 

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al.,  ​2020).  Hence,  aerosol  and  fomite  transmission  of  SARS-CoV-2  is  highly plausible, acting 
as an echo to SARS-CoV transmission historically.  
 
Fecal-oral  transmission  has  also  been  suggested,  although  exact  gastrointestinal 
interactions  have  not  yet  been  fully  elucidated  (Hindson,  2020).  ACE2  mRNA  is  highly 
expressed  in  the  gastrointestinal  system,  which  follows  a  similar  pattern  as  the  pulmonary 
infection.  ​Consequently,  some  patients  presented  with  ​digestive  systems  as  their  chief 
complaint.  In  73  hospitalized  patients,  39  patients  tested  positive  for  COVID19  from  stool 
samples  by  RT-PCR  (Hindson,  2020).  Other  pertinent  findings  were  that  live  viruses  were 
found  in  stool  samples  of  patients  who  did  not  have  diarrhea,  and  that  some  patients 
remained  positive  for  SARS-CoV-2  in  stool  even  after  testing  negative  from  their  respiratory 
samples.  These  findings  underpin  the  emphasis  on  good  personal  hygiene,  especially  since 
the virus can also be spread by asymptomatic individuals.  
 
The  ​high  transmissibility  of  SARS-CoV-2  is  attributed  to  viral  spread  via 
asymptomatic-infected  individuals,  originally  reported  in  Germany  (Prompetchara  ​et  al., 
2020).  Mean  incubation periods last from 2-11 days with viral shedding beginning 24-48 hours 
prior  to  symptoms,  thus  providing  a  long  window  of  time  for  undetected  transmissions  to 
occur.  Mathematical  models  have  been  constructed  to  consider  the  virus’s  ​Reproductive 
Number​, or ​R0​​ , that illustrates the average number of people one infected individual can pass 
the  virus  to.  If  R​0  >
​   1,  the  virus’s  prevalence  is  increasing.  Thus,  the  goal  is  to  attain a number 
below  1  to  stop  further  transmission.  SARS-CoV-2’s  R​0  ​as  of  ​February  20,  2020 was at ​2.2-2.6, 
implicating  that  on  the  average,  one  asymptomatic  person  can  pass  the  virus  to 
approximately  2-3  other  people  (Prompetchara  ​et  al.,  ​2020).  This  number  is  important  to 
compare  the  transmissibility  of  COVID-19  in  relation  to  previous  epidemics---  SARS-CoV  and 
MERS-CoV.  
 
Prompetchara  ​et  al.  ​(2020)  compared  infection  and  mortality  data  on  SARS-CoV, 
MERS-CoV,  and  COVID19  found  on  ​Figure  1.7​.  In  addition,  higher  viral  loads  and  longer  viral 
shedding  both  point  to  greater  severity  of  cases,  with  up  to  60  times  higher  viral  load  than 
mild cases (Liu e ​ t al., ​2020).  
 

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Figure 1.7. ​Comparative data of (A) deaths/total cases and (B) mortality of SARS-CoV, 
MERS-CoV, and SARS-CoV 2/COVID19 (Prompetchara et al., 2020) 
 
There  is  currently  no  clear  and  direct  evidence  that  points  to  the  transmission  of 
SARS-CoV-2  from  mothers  to  their  babies  in-utero.  Despite  this,  one  infant  presented  with 
high  IgG  and  IgM  levels  as  early  as  2  hours  of  age,  with  elevated  cytokines  and  liver  injury, 
implying  the  possibility  of  neonatal  transmission  (Schwartz,  2020).  Findings  report  the 
absence  of  viral  RNA  in  vaginal  secretions;  however,  a  lot  of  those  with  concurrent  infection 
and  undergoing  labor  opted  for  C-section.  Amniotic  fluid,  breast  milk,  and  cord  blood  all 
tested  negative  for  SARS-CoV-2.  Current  protocol  suggested  by  WHO  does  not  recommend 
early cord clamping. 
 
Although  the  WHO  does  not  recommend  early  cord  clamping  in  infected  mothers, 
infant  infection  via  contact  with  infectious  respiratory  secretions  is  still  concerning.  It  is 
recommended  by  CDC  that  mothers  take  precautionary  measures  to  prevent  COVID-19 
transmission  through  other  means  such  as  proper  hand  hygiene  and  wearing  masks  upon 
breastfeeding.  It  is  also  not  recommended  for  infected  mothers  to  directly  breastfeed  their 
newborns up to 14 days to give way for viral shedding. 
 
Immune Response 
Immunopathology  
Thus  far,  known  immunopathological  effects  of  COVID-19  are  the  development  of 
lymphopenia  and  ​pneumonia  along  with  characteristic  ​ground  glass  opacity  changes  in 
chest  ​CT  scans  observed in patients (Prompetchara ​et al., ​2020). A ​cytokine storm also takes 
place  with  the  following  proponents:  IL-2,  IL-6,  IL-7,  IL-10,  G-CSF,  IP10,  MCP-1,  MIP-1A,  and 
TNF⍺.  The  presence  of  a  cytokine  storm  supports  the  induction  of  viral  sepsis  and 
inflammatory-induced  lung  injury,  pointing  towards  ​other  respiratory  complications  such 
as  pneumonitis,  acute  ARDS,  respiratory  failure,  shock,  and  organ  failure.  Therapies  that 
target  these  receptors,  such  as  ​Tocilizumab  which  blocks  the  IL-6  receptor,  can  partially 
block the cytokine storm and potentially prevent further complications. 
 
SARS-CoV-2  is  also  speculated  to  have  ​immune evasion mechanisms​, explaining the 
longer  incubation  period  (2-11  days).  Adaptive  immune  evasion  was  found  in  MERS-CoV,  via 
MHC  Class  I  and  II  downregulation  during  macrophage  infection,  but  this  is  not  observed  in 
SARS-CoV-2.  The  Betacoronavirus  genus  all  share  mechanisms  that  inhibit  type  I  IFN 
signaling,  suspected  to  be  present  in  SARS-CoV-2.  It  is  important  to  note  that  many  of  the 
immune mechanisms are based on these shared traits among coronaviruses.  
 
Due  to  these  reasons,  ​the  elderly  and  those  with  ​comorbidities  are  more  severely 
affected,  while  younger  individuals  tend  to  be  more  resistant  to  deleterious  consequences. 
Hypertension,  diabetes, and cardiovascular diseases are some of the most notable comorbids 
(Prompetchara e ​ t al., ​2020). Specific details on these immune responses are discussed below.  
 
Innate Immune Response 
An  appropriate  viral  response  is  mounted  upon  viral  entry:  recognition  of 
pathogen-associated  molecular  patterns  (PAMPS),  followed  by  an  intracellular  cascade 
that  activates  NF-κB  and  IRF3.  These  transcription  factors  lead  to  expression  of  ​Type  I  IFN 

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and  other  pro-inflammatory  cytokines,  comprising  the  first  line of defense at the entry site. 

IFN-stimulated  gene  (ISG)  expression  mounted  by type I IFN should be able to contain viral 
replication  and  dissemination  this  early  on.  This  exact  mechanism  is ​delayed in SARS-CoV-2, 
just  as  it  is  also  suppressed  in  SARS-CoV  and  MERS-CoV.  The  higher  the  dampening  of  this 
response,  the  greater  the  severity  of  the  disease  (Prompetchara  ​et  al.,  ​2020).  Further 
evidence  shows  ​dysregulated  type  I  IFN  and  inflammatory  monocyte-macrophage 
infiltration  ​as  the  main causes of ​lethal pneumonia​. SARS-CoV has previously been reported 
to  infect  macrophages  and  T-cells  as  an  integral  part  of  its  pathogenesis.  Whether  or  not 
SARS-CoV-2 infects particular immune cells is still unknown.  
 
Increased  ​neutrophil  and  decreased  lymphocyte  ​counts  ​correlate  to  ​disease 
severity  and  death  (Prompetchara  ​et  al.,  ​2020).  Their  production  of  cytokines  support  cases 
of ICU patients that present with higher numbers of pro-inflammatory cytokines. 
 
Adaptive Immune Response 
Since  SARS-CoV-2  is  a  new  virus,  there  are  no  pre-existing  antibodies  to  confer 
immunity.  There  is  also  only  trivial  cross-reactivity  between  SARS-CoV-2  and  the  previous 
coronaviruses.  B  cells, in coordination with antigen-presenting cells, orchestrate the ​humoral 
response  against  the  virus  through  the  ​Spike  ​protein​.  This  same  protein  is  also  the  main 
focus of ​enzyme-linked immunosorbent assays (ELISA)​ for detection (Amanat e ​ t al., ​2020).  
 
Seroconversion  comparisons  between  the  three  viruses  are  also  integral,  as  delayed 
and weak antibody responses are associated with severe outcomes. Preliminary studies show 
that  ​IgM  ​peaks  at  day  9  after  disease  onset,  then  to  ​IgG  peaks  by  the  ​2nd  week  (day  14). 
SARS-CoV  exhibits  seroconversion  as  early  as  day  4,  while  MERS-CoV  undergoes  conversion 
only  by  the  2nd  or  3rd  week  (Prompetchara  ​et  al.,  ​2020).  In  relation,  certain  steps have been 
made  to  produce  test  kits  primed  on  detecting  antibodies  from  the  virus,  to be discussed in 
the later modules.  
 
The  ​Th1  type  immune  response is the ​dominant response against SARS-CoV-2, as it is 
in generally all viral infections. Helper T cells direct the responses as cytotoxic T cells eliminate 
infected  cells.  CD8  was  found  to  have  higher  responses  in  SARS-CoV  and  MERS-CoV 
compared  to  CD4  responses,  and  is  suspected  to  be  the  similar  response  for  SARS-CoV-2 
(Prompetchara  ​et  al.,  ​2020).  Although  crucial,  CD8  responses  must  still  be  mitigated  in 
preventing lung pathology. In line with this, virus-specific T-cell responses in severe cases had 
more  polyfunctional  CD4  and  CD8  T  cells.  Furthermore,  higher  Th2  cytokines  (i.e.  IL-4,  IL-5, 
IL-10)  were  observed. Refer to ​Table 1.1 ​for a summary of transmission dynamics and immune 
responses among SARS-CoV, MERS-CoV, and SARS-CoV-2. 
 
Table 1.1​ ​Summary of Transmission Dynamics and Immune Responses (Parts of the table 
are taken from Prompetchara et al., 2020)  
Demographic/  SARS-CoV  MERS-CoV  SARS-CoV-2 
Characteristic 

First Place of  Guangdong, China  Jeddah, Saudi Arabia  Wuhan, China 
Detection 

11 
 

Mortality Rate  9.19%  34.4%  2.8%* 

Possible Natural  Bat  Bat  Bat 

Reservoirs 

Possible  Palm Civets  Camel  Pangolin 

Intermediate Hosts 

Predominant Cell  ACE2  Dipeptidyl Peptidase  ACE2 

Receptor  4 (DPP4) 

Feco-Oral  Present  Present   Suspected  

Transmission  

Immune Evasion  Type I IFN Signal  MHC Class I and II  Type I IFN Signal 
Mechanism  Inhibition  Downregulation  Inhibition   

Immune Cell  Macrophages/  Macrophages/  Unknown 

Infection  T-cells  T-cells 

Seroconversion  IgG: 9th day  IgG: 2nd or 3rd  IgG: 14th day 
TIme  week 
*Not yet finalized. 

Summary of Key Concepts 

 
● COVID-19 w ​ as first reported in Wuhan, China in December, 2019 and declared a 
global p ​ andemic​ by WHO on ​March 11, 2020. 
● The COVID-19 virus contains a ​96% genetic similarity​ to a SARS-like coronavirus 
that infects bats. 
● Genetic  polymorphisms  affecting  the  viral  ​S  protein  in  COVID-19  can  cause  ​lethal 
human diseases​ such as SARS and MERS. 
● S  protein  ​found  on  COVID-19  ​is  responsible  for  viral  attachment  and  facilitation  of 
endocytosis by cells expressing the A ​ CE2 receptor. 
● In the lungs, COVID-19 primarily infects ​type II pneumocytes. 
● Viral  ​transmission  is  predominantly  accomplished  through  ​person-to-person 
transmission by ​inhalation and other means of ​exposure to droplets ​from infected 
individuals. 
● COVID-19  possesses  significantly  ​higher  transmission  rates  than  SARS-CoV  and 
MERS-CoV. 
● Due  to  ​immune  evasion  mechanisms  such  as  inhibited  ​Type  I  IFN  signaling,  ​the 
elderly​ and those with c ​ omorbidities​ are more severely affected by COVID-19. 
● IgM  ​antibodies  typically  peak  by  day  9  after  disease  onset,  then  switches  to  ​IgG  by 
the ​2nd week. 

 
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