GENETIC GATEWAYS TO

COVID-19 INFECTION:

IMPLICATIONS FOR RISK,

SEVERITY, AND OUTCOMES

Kar ine Eyng

Lui s F e l i pe Range l

Ma theus Mi randa

Ra fae la To ledo

Vini c ius S i l va Costa

Seminar 1

Universidade de São Paulo – Faculdade de Medicina de Ribeirão Preto

PORTAS DE ENTRADA GENÉTICAS PARA A

INFECÇÃO POR COVID-19: IMPLICAÇÕES PARA RISCO, GRAVIDADE E RESULTADOS

SUMMARY

1) INTRODUCTION

2) Role of population genomics in covid-19 pandemics

3) Role of angiotensin-converting enzyme 2 gene in entry of SARS-CoV-2: The first genetic gateway

4) HLA, antigen presentation, and protective immunity in SARS-CoV-2 infection:The second genetic gateway

5) Genetic underpinning of the cytokine storm: The 3rd genetic gateway

6) TLR-pathway in SARS-CoV-2 infection

7) Complement activation pathway in SARS-CoV-2 infection

8) CONCLUSION

INTRODUCTION

• COVID-19: severe acute respiratory syndrome caused by SARS-CoV-2

• Signif icant variation in the symptom profi le and severity → risk factors: age and

co-morbidit ies, including diabetes, obesity, cardiovascular and cerebrovascular

diseases

• genetic background: determining susceptibil ity or resil ience to viral infections

→ host recognition of the viral particles; presentation of viral peptides to the

immune system and neutralization of the infection

• In this article, three genetic gateways to covid-19 infections are proposed

• Probably, there is a combination between environmental and genetic factors that

explain the dynamic of the infection and the discrepancies between the cases

Rafaela Toledo

Role of population genomics in

covid-19 pandemics

▪ Popu lat ion genomics p lays an impo r tant ro le in genet ic

landscap ing o f popu lat ions and prov id ing in fo rmat ion

about suscept ib i l i ty and pro tect ion against in fect ious

d iseases.

▪ Cur rent ly, there are no genet ic data to suppo r t

ethn ic /geograph ical var iat ion o f COVID -19 on g lobal

bas is .

▪ Prel iminary analyses suggest an impor tant ro le o f host

genet ics , especial ly genes regu lat ing the immune

response in the r isk and sever i ty o f SARS -CoV-2

in fect ion

Karine Eyng

Role of angiotensin-converting enzyme 2 gene

in entry of SARS-CoV-2: The first genetic gateway

▪ I t became c lear that SARS-CoV-2 uses the angiotensin -2

converting enzyme (ACE2), a lso a SARS -CoV receptor, for en try

in to the host ce l l.

▪ A struc tu ra l modeling study predic ted that certa in ACE2 var ian ts

migh t prov ide poten tia l resistance to SARS -CoV-2 in fec tion .

▪ Th is study fu rther demonstrated that dif ferences in a l le le

f requenc ies of eQTLs of ACE2 observed in dif feren t popu lations

cou ld account for diversity of expression pattern of ACE2 gene

in popu lations.

Karine Eyng

Role of angiotensin-converting enzyme 2 gene

in entry of SARS-CoV-2: The first genetic gateway

▪ The au thors reported var iable ACE2 gene expression among var ious

popu lations, however, magn itude of dif ferences seems to be small.

▪ Further ana lysis of popu lation genetics data re lated to ACE2 gene

var iations and the ir impact on the re lative leve ls of its spl ice var ian ts

f rom indiv idua ls inhabiting COVID -19 hotspots shou ld prov ide more

insigh ts in to the role of ACE2 gene in susceptibi l ity or resistance to

SARS-CoV-2 in fec tion .

▪ Hypertension and D iabetes mell itus (DM) are the most common

comorbid conditions in COVID -19; both these conditions are modu lated

by ACE2.

▪ A key role of ACE2 has a lso been demonstrated in in f lammatory

processes.

Karine Eyng

HLA, antigen presentation, and protective immunity

in SARS-CoV-2 infection:The second genetic gateway

• The Human Leukocyte Antigen (HLA) system

is encoded by the Major Histocompatib i l ity

Complex (MHC), a large genomic reg ion with

thousands of polymorphisms.

• After infection, antigen presenting cel ls

(APCs) carry out phagocytosis of the

pathogen, after d igestion the MHC molecules

carry and present the pathogenic peptides

on their surface to be recognized by the T

lymphocyte receptors that wi l l e l iminate the

invader.

Vinícius S. Costa

HLA, antigen presentation, and protective immunity in

SARS-CoV-2 infection:The second genetic gateway

• Several stud ies have been carr ied out to d iscover the influence that HLA d iversi ty exerts

on d ifferent degrees of immune response, but the results were inconc lusive.

• Although it is not known which genes harm and which improve in combating SARS-CoV-2,

i t is known that their var iety regulates a d iscrepancy between different responses to the

virus.

• HLA molecules can confer susceptib i l i ty or resistance to infections, so they are considered

a gateway to the coronavirus.

Vinícius S. Costa

Genetic underpinning of

the cytokine storm: The

3rd genetic gateway

• SARS-CoV-2 infection leads to a cytokine storm and

then an exacerbated inflammatory response.• higher levels of IL-6 (~80 pg/mL) were correlated with

a 22 times greater risk of respiratory failure in COVID-19 patients.

• T lymphocytes are prolific producers of cytokines. The development, differentiation, and activation of T lymphocytes and production of cytokines are controlled by genetic as well as epigenetic processes.

Luís Felipe Rangel

• Cytokine gene polymorphisms confer risk or protection to infectious diseases.

• Until now, there are no studies on the impact of cytokine gene polymorphisms on the risk of SARSCoV-2. However, given an important role of genetic background in determining the pattern of inflammatory response, and a critical role of cytokines in influencing the severity of COVID-19, genetic factors regulating inflammation seems to play an overarching role in COVID-19.

• Allelic variations in cytokine genes in global populations show a strong latitudinal impact.

• Vitamin D plays an important role in maintaining the immune homeostasis.• There is a possibility that vitamin D status in the populations across

continents might have some influence on geographical variance of COVID-19.

• Vitamin D diminish the production of proinflammatory cytokines including TNF-a, IFN-y, etc. and induce the expression of anti-inflammatory cytokines.

• Possibly, vitamin D is critically involved in regulating cytokine storm and the outcome of COVID-19.

• However, Cytokine expression depends on various upstream regulators, such as TLR and other components of innate immunity, such as complement components.

Luís Felipe Rangel

TLR-pathway in SARS-CoV-2 infection

•TLR signaling plays critical role in the regulation of cytokine expression in the

immune system.

•Mice deficient in certain TLRs are more susceptible to SARS-COV infection.

•Currently, there are no studies on the role of TLR pathway in SARS-COV-2 infection.

•Previous studies suggest that genetic variation within TLR or components of TLR

pathway influenced SARS-COV infection.

•TLR genes exhibit a distinct population distribution.

•TLR genes could emerge as a crucial determinat of differencial susceptibi l ity to

SARS-COV-2 infection and severity.

Matheus M. Anjos e Silva

Complement activation pathway in SARS-CoV-2 infection

•Complement components interact with TLRs and promote the development of

inflammatory cells.

•Complement components have important implicat ion in the induction of the

cytokine storm and inflamation in SARS-COV-2 infect ion.

•There are no data on the impact of complement gene variat ion on the risk and

severity of SARS-COV-2 infect ion.

•TLR, cytokines and genes controlling the function of the

complement pathway could provide important pointers to the magnitude of

inflamatory responses in COVID-19.

Matheus M. Anjos e Silva

CONCLUSION

• Some of the genes responsible for the host ’s immune system can interfere on the

severity/resistance of the infect ion and those genes are dif ferent ly distributed

around the world

• Comorbidit ies, age, sun exposure, temperature and other environmental variables

are important in the response to the virus

• There is no proof that ant iretrovira ls, ant imalaria ls and BCG vaccines are eff icient

• Socia l and economic factors are really important to the morta lity rate

• It is important to evaluate all these factors that are linked to the dynamics of the

covid to be able to f ight the pandemic in the best way

Rafaela Toledo