ABO Blood Groups and SARS-CoV-2 Infection by Fumiichiro Yamamoto, Ph.D.

Fumiichiro (Fumi) Yamamoto, Ph.D.
Immunohematology & Glycobiology Laboratory
Josep Carreras Leukaemia Research Institute
ABO Blood Groups and
SARS-CoV-2 Infection
March 26, 2020

Disclosure
Relevant Financial Relationship:
None
Off-Label Usage:
None
Fumiichiro Yamamoto, Ph.D.
The opinions expressed in this presentation are the author's own and do
not reflect the view of Josep Carreras Leukaemia Research Institute.

1. What is the ABO blood group system?
2. A and B antigens are expressed on cells other than RBCs.
3. Coronavirus Disease 2019 (COVID-19)
4. Coronaviruses and SARS-CoV-2
5. SARS-CoV-2 viruses express A and/or B antigens depending
on the ABO phenotype of cells in which they are produced.
6. Presence/absence of Anti-A, Anti-B, and/or Anti-A,B
antibodies affects individual’s susceptibility to SARS-CoV-2
infection.
7. What is the medical implication of the association?
Topics

What is the ABO blood group
system?

- +
Finding of RBC agglutination
(Karl Landsteiner, 1900)
Discovery of ABO Blood Groups
RBC Dr.
Störck
Dr.
Pletschnik
Dr.
Sturli
Dr.
Erdheim
Mr.
Zaritsch
Mr.
Landsteiner
Plasma
Dr. Störck - + + + + -
Dr. Pletschnik - - + + - -
Dr. Sturli - + - - + -
Dr. Erdheim - + - - + -
Mr. Zaritsch - - + + - -
Mr. Landsteiner - + + + + -
Safe Blood Transfusion
Individuals can be grouped.

Blood group Antigen Antibody
A A Anti-B
B B Anti-A
AB A + B -
O - Anti-A + Anti-B
Individuals who do not express the A and/or B
antigen(s) possess corresponding antibodies.
(Landsteiner’s Law)
ABO Blood Group System

Blood group Antigen Antibody
A A Anti-B
B B Anti-A
AB A + B -
O - Anti-A + Anti-B
Anti-A,B
Individuals who do not express the A and/or B
antigen(s) possess corresponding antibodies.
(Landsteiner’s Law)

ABO blood group system consists of:
Immunology & Immunohematology
Anti-A antibody Anti-B antibody
Anti-A,B antibody
Gal 1-3 (Fuc 1-2) Gal-GalNAc 1-3 (Fuc 1-2) Gal-
A antigen B antigen

(Source: Wikipedia)
ABO Blood Type Distribution
ABO Phenotype Distribution in Spain
A B AB O
42 10 3 45 (%)
Human Genetics

A and B antigens are expressed on cells
other than RBCs.

(Wikipedia)
Expression of A and B Antigens

Coronavirus Disease 2019
(COVID-19)

*An infectious disease caused by "severe acute respiratory
syndrome coronavirus 2" (SARS-CoV-2)
*First identified in 2019 in Wuhan, China, and has since spread
globally, resulting in the 2019–20 coronavirus pandemic.
*Common symptoms include fever, cough, and shortness of
breath, and less common muscle pain, sputum production and
sore.
*While the majority of cases result in mild symptoms, some
progress to severe pneumonia, multi-organ failure, and death.
(Wikipedia)
Coronavirus disease 2019 (COVID-19)

*The infection is typically spread via respiratory droplets
produced during coughing and sneezing.
*Time from exposure to onset of symptoms is generally between
2 and 14 days, with an average of 5 days.
*Recommended measures to prevent infection include
frequent hand washing, maintaining distance from others (social
distancing), and keeping hands away from the face.
*At this moment there is no vaccine or specific antiviral
treatment effective for COVID-19.
(Wikipedia)
Coronavirus disease 2019 (COVID-19)

Total confirmed
cases
Total deaths Recovered
Worldwide 480,446 21,571 115,850
China 81,782 3,291 74,177
Iran 29,406 2,234 10,457
South Korea 9,241 131 4,144
Japan 1,307 45 310
Italy 74,386 7,503 9,362
Spain 49,515 3,647 5,367
USA 69,197 1,046 619
March 26, 2020 (12:00pm Spanish peninsular time)
Center for Systems Science and Engineering (CSSE) at Johns Hopkins University
(https://www.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6)
COVID-19 Cases and Deaths

*The name ”coronavirus” is derived from the Latin ”corona”,
which refers to the characteristic appearance reminiscent of
a solar corona around the virus particles, due to the surface
covering in club-shaped Spike (S) proteins.
*Human coronaviruses have been involved in serious
respiratory tract infections, including SARS-CoV responsible
for Severe Acute Respiratory Syndrome (SARS) in
2003, MERS-CoV responsible for Middle East Respiratory
Syndrome (MERS) in 2012, and SARS-CoV-2 responsible
for COVID-19 in 2019-2020.
Coronaviruses
(Wikipedia)

Coronaviruses
(Wikipedia)
Illustration of the morphology of coronaviruses Microscopy image showing SARS-CoV-2

*Severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) is a positive-sense single-stranded RNA virus with the
30kb genome size and 10 genes.
*It is contagious in humans and is the cause of the ongoing
pandemic of coronavirus disease 2019 (COVID-19).
*SARS-CoV-2 has close genetic similarity to bat
coronaviruses, from which it likely originated. An intermediate
animal reservoir such as a pangolin is also thought to be
involved in its introduction to humans.
(Wikipedia)
Severe Acute Respiratory Syndrome Coronavirus 2

*SARS-CoV-2 virus is
membrane-encapsulated
and has four structural
proteins: S (spike), E
(envelope), M (membrane),
and N (nucleocapsid). The
N protein holds the RNA
genome, and the S, E,
and M proteins together
create the viral envelope.
(Wikipedia)
SARS-CoV-2 Virus
Spike (S)
Glycoprotein
Glycans
(A, B, A&B, -)

*Spike (S) protein is a large transmembrane protein that
mediates cellular association (Li W, et al. 2006).
*The S protein possesses 23 N-linked glycosylation sites, and
the glycosylation has been confirmed of 13 of these sites
(Krokhin O, et al. 2003; Ying W, et al. 2004).
*SARS-CoV was shown to bind human angiotensin-converting
enzyme 2 (ACE2) with high affinity (Xiao X, et al. 2003; Wong SK,
et al. 2004).
*The S protein’s association with ACE2 protein was also shown
of SARS-CoV-2 (Wrapp D, et al. 2020).
SARS-CoV Spike Protein

*Transmembrane protease TMPRSS2 cuts open the Spike
protein, exposing a fusion peptide. The virus then releases RNA
into the cell, producing viral copies that are disseminated to
infect more cells (Hoffman M, et al. 2020, Matsuyama S, et al 2020).
SARS-CoV-2 Spike Protein
(NCBI)
Closed state =>
(MMDB ID: 185171 PDB ID: 6VXX)
<= Open state
(MMDB ID: 185172 PDB ID: 6VYB)

SARS-CoV-2 viruses express A
and/or B antigens depending
on the ABO phenotype of cells
in which they are produced.

Major histocompatibility complex (MHC) locus
The HLA-B*4601 haplotype was associated with severity of
SARS infection in a group of Taiwanese patients (Lin M, et al,
2003).
The HLA-B*0703 and HLA-DRB1*0301 haplotypes were
associated with severity of SARS infection in a group of
Hong Kong Chinese patients (Ng MH, et al. 2004).
ABO blood group locus
Blood type O was associated with a lower risk of SARS
infection (Cheng et al. 2005).
Genetic Factors Influencing SARS-CoV Infection

A and/or B Antigen Expression on SARS-CoV
Fact:
*SARS-CoV replicates in epithelial cells of the respiratory and
digestive tracts that have the ability to synthesize A and/or B
glycan antigens, depending on individual’s ABO phenotype.
Assumptions:
*The S proteins produced in A, B, or AB individuals could be
decorated with A, B, or A/B glycan antigens, respectively.
*Anti-A, Anti-B, and Anti-A,B antibodies could bind to the A, B,
and A/B antigens on the S proteins, respectively, and block
the interaction between S and ACE2 proteins.

Inhibition of Interaction between S & ACE2 Proteins
Inhibition of the interaction between the SARS-CoV Spike protein
and its cellular receptor by anti-histo-blood group antibodies
Patrice Guillon et al. (2008). Glycobiology, 18(12): 1085-1093.
https://doi.org/10.1093/glycob/cwn093
Abstract
Severe acute respiratory syndrome coronavirus (SARS-CoV) is a highly pathogenic emergent virus which replicates in cells that
can express ABH histo-blood group antigens. The heavily glycosylated SARS-CoV spike (S) protein binds to angiotensin-
converting enzyme 2 which serves as a cellular receptor. Epidemiological analysis of a hospital outbreak in Hong Kong revealed
that blood group O was associated with a low risk of infection. In this study, we used a cellular model of adhesion to
investigate whether natural antibodies of the ABO system could block the S protein and angiotensin-converting
enzyme 2 interaction. To this aim, a C-terminally EGFP-tagged S protein was expressed in chinese hamster ovary cells
cotransfected with an α1,2-fucosyltransferase and an A-transferase in order to coexpress the S glycoprotein ectodomain and the
A antigen at the cell surface. We observed that the S protein/angiotensin-converting enzyme 2-dependent adhesion of these
cells to an angiotensin-converting enzyme 2 expressing cell line was specifically inhibited by either a monoclonal or human
natural anti-A antibodies, indicating that these antibodies may block the interaction between the virus and its receptor, thereby
providing protection. In order to more fully appreciate the potential effect of the ABO polymorphism on the epidemiology of
SARS, we built a mathematical model of the virus transmission dynamics that takes into account the protective effect of ABO
natural antibodies. The model indicated that the ABO polymorphism could contribute to substantially reduce the virus
transmission, affecting both the number of infected individuals and the kinetics of the epidemic.

Cell model experiments:
*Chinese hamster ovary cells were engineered to express, on
cell surface, S proteins carrying A glycan antigens.
*The adhesion of those cells to Vero E6 cells expressing ACE2
was specifically inhibited by a mouse monoclonal Anti-A
antibody or human natural Anti-A antibodies.
Analysis of viral transmission dynamics:
*The mathematical model indicated that the ABO polymorphism
could substantially reduce viral transmission, affecting both the
number of infected individuals and the kinetics of the epidemic.
Anti-A Antibodies Blocked S-ACE2 Interaction

Presence/absence of Anti-A,
Anti-B and/or Anti-A,B
antibodies affects individual’s
susceptibility to SARS-CoV-2
infection.

ABO Polymorphism and SARS-CoV-2 Infection
Relationship between the ABO Blood Group and the COVID-19
Susceptibility
Jiao Zhao et al. medRxiv preprint doi: https://doi.org/10.1101/2020.03.11.20031096.
Abstract
OBJECTIVE: To investigate the relationship between the ABO blood group and the COVID-19 susceptibility. DESIGN:
The study was conducted by comparing the blood group distribution in 2,173 patients with COVID-19 confirmed by SARS-CoV-2 test from three hospitals in Wuhan and
Shenzhen, China with that in normal people from the corresponding regions. Data were analyzed using one-way ANOVA and 2-tailed χ 2 and a meta-analysis was performed
by random effects models. SETTING: Three tertiary hospitals in Wuhan and Shenzhen, China. PARTICIPANTS: A total of 1,775 patients with COVID-19, including 206 dead
cases, from Wuhan Jinyintan Hospital, Wuhan, China were recruited. Another 113 and 285 patients with COVID-19 were respectively recruited from Renmin Hospital of
Wuhan University, Wuhan and Shenzhen Third People’s Hospital, Shenzhen, China. MAIN OUTCOME MEASURES: Detection of ABO blood groups, infection occurrence of
SARS-CoV-2, and patient death. RESULTS: The ABO group in 3694 normal people in Wuhan showed a distribution of 32.16%,
24.90%, 9.10% and 33.84% for A, B, AB and O, respectively, versus the distribution of 37.75%, 26.42%, 10.03% and
25.80% for A, B, AB and O, respectively, in 1,775 COVID-19 patients from Wuhan Jinyintan Hospital. The proportion
of blood group A and O in COVID-19 patients were significantly higher and lower, respectively, than that in normal
people (both P < 0.001). Similar ABO distribution pattern was observed in 398 patients from another two hospitals in Wuhan and Shenzhen. Meta-analyses on the
pooled data showed that blood group A had a significantly higher risk for COVID-19 (odds ratio-OR, 1.20; 95% confidence interval-CI 1.02~1.43, P = 0.02) compared with non-
A blood groups, whereas blood group O had a significantly lower risk for the infectious disease (OR, 0.67; 95% CI 0.60~0.75, P < 0.001) compared with non-O blood groups.
In addition, the influence of age and gender on the ABO blood group distribution in patients with COVID-19 from two Wuhan hospitals (1,888 patients) were analyzed and
found that age and gender do not have much effect on the distribution. CONCLUSION: People with blood group A have a significantly higher risk for acquiring COVID-
19 compared with non-A blood groups, whereas blood group O has a significantly lower risk for the infection compared with non-O blood groups.

Relationship between the ABO Blood Group and the COVID-19
Susceptibility
Jiao Zhao et al. medRxiv preprint doi: https://doi.org/10.1101/2020.03.11.20031096.
CONCLUSION:
*People with blood group A have a significantly higher risk for
acquiring COVID-19 compared with non-A blood groups.
*People with blood group O have a significantly lower risk for the
infection compared with non-O blood groups.
ABO Polymorphism and SARS-CoV-2 Infection

What is the medical implication
of the association?

A individual B individual AB individual O individual
A virus B virus AB virus O virus
A antigen B antigen A & B antigens None
Anti-A Anti-B None Anti-A Anti-B
Anti-A,B
SARS-CoV-2 Infectivity

ABO Phenotype of Virus
A B AB O
Frequency 0.32 0.25 0.09 0.34
ABOTypeof
Individual
A 0.32 0.0103427 0.0080078 0.0029266 0.0108829
B 0.25 0.0080078 0.0062001 0.0022659 0.0084262
AB 0.09 0.0029266 0.0022659 0.0008281 0.0030794
O 0.34 0.0108829 0.0084262 0.0030794 0.0114515

ABO Calculated Actual
Type Inhibition
0% 25% 50% 75% 100%
A 32.16 33.03 34.13 35.60 37.63 37.75
B 24.90 25.06 25.27 25.55 25.93 26.42
AB 9.10 10.21 11.64 13.52 16.13 10.03
O 33.84 31.70 28.96 25.33 20.30 25.80

*Anti-A, Anti-B, and Anti-A,B antibodies may decrease
individual’s chance of infection to SARS-CoV-2 virus, resulting
in a lower susceptibility of type O individuals.
*Blockage may be complete or not. However, once infection is
established, individuals produce viruses of their own ABO
types, and Anti-A, Anti-B, and/or Anti-A,B antibodies they
possess may no longer neutralize newly produced viruses.
*O individuals may have a lower risk of viral infection, but type
O SARS-CoV-2 viruses they produce may infect to their own
cells as well as individuals with any ABO phenotypes.

*Anti-A, Anti-B and/or Anti-A,B IgA antibodies in the respiratory
tract may be primarily responsible for mucosal immunity
although those of IgM and IgG classes may also function.
*The inhibition of SARS-CoV-2 viral infection may diminish the
R0 value, namely, the expected number of cases directly
generated by one case in a population susceptible to infection.
*The inhibition in viral transmission is less effective in a
population homogeneous in the ABO phenotype, for instance,
Amerindians in Brazil and other countries in the Central/South
America where type O is prevalent.

ABO-dependent Susceptibility to Other Diseases
Venous thromboembolism (VTE, Economy class syndrome)
ABO-dependent serum concentrations of von Willebrand Factor
(vWF) and Coagulation Factor VIII (FVIII)
Low concentrations in group O => Low disease incidence
Severe brain malaria
ABO-dependent adhesion of RBCs infected with malaria parasite
(Plasmodium falciparum)
Weak adhesion of group O RBCs => Low disease incidence
Gastric ulcer
One of Helicobacter pylori’s adhesion receptors to stomach
epithelium is Lewis b (Leb). Functional A and B transferases convert
it to ALeb and BLeb, to which the bacteria bind less efficiently.
Strong adhesion to group O cells => High disease incidence

Anti-A, Anti-B and/or Anti-A,B antibodies may inhibit the
interaction between the viral S proteins and cellular ACE2
receptors.
This may trigger:
*Prevention of the entry and opsonization of SARS-CoV-2
virus into cells and the viral neutralization in a complement-
mediated manner.
*Generation of cytotoxic T cells may be promoted.
*Acquisition of immunity against other viral antigens may
follow.

Useful Literature
Relationship between the ABO Blood Group and the COVID-19 Susceptibility.
Zhao J, Yang Y, Huang H-P, Li D, Gu D-F, Lu X-F, Zhang Z, Liu L, Liu T, Liu Y-K, He
Y-J, Sun B, Wei M-L, Li Y-R, Yang G-Y, Wang X-H, Zhang L, Zhou X-Y, Xing M,
Wang PG. (2020). medRxiv preprint. https://doi.org/10.1101/2020.03.11.20031096.
Inhibition of the interaction between the SARS-CoV Spike protein and its
cellular receptor by anti-histo-blood group antibodies.
Guillon P, Clément M, Sébille V, Rivain JG, Chou CF, Ruvoën-Clouet N, Le Pendu
J. (2008). Glycobiology, 18(12):1085-1093. https://doi.org/10.1093/glycob/cwn093
ABO research in the modern era of genomics.
Yamamoto F, Cid E, Yamamoto M, Blancher A. (2012). Transfus Med Rev. 26(2):
103-18. https://doi.org/10.1016/j.tmrv.2011.08.002.
Molecular genetics to genomics – historical overview of the ABO research.
Yamamoto F. (2019). ISBT Sciences. PL‐02‐02. https://doi.org/10.1111/voxs.12525.

Acknowledgment
I would like to thank Miyako Yamamoto for her assistance
in the preparation of this presentation.
I would also like to thank you for your attention.

ABO Blood Groups and SARS-CoV-2 Infection by Fumiichiro Yamamoto, Ph.D.

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