Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : July 29, 2020
Accepted : August 27, 2020
Published online : September 30, 2020
doi:10.24659/gsr.7. 3_232

Review article

Why are people with glycative stress so susceptible to COVID-19 infection?
Kyle Haasbroek, Masayuki Yagi, Yoshikazu Yonei
Anti-Aging Medical Research Center/Glycative Stress Research Center, Graduate School of Life and Medical Sciences,
Doshisha University, Kyoto, Japan

Abstract

People with diabetes show an increased susceptibility to infection by SARS-CoV-2, greater incidence of pneumonia, andworse clinical outcomes. As diabetes involves high glycative stress, here we present a review of the literature regarding thepotential interactions of glycative stress and COVID-19 that may help to explain some of the observed differences in outcomesof diabetic patients. Glycative stress directly suppresses immune function, leaving the body less able to deal with infection.
Increased colonization of potentially pathogenic bacteria, mediated by glycative stress, such as Staphylococcus aureus, mayalso lead to negative outcomes during infection. The presence of S. aureus on the skin may weaken its barrier function andincrease the risk of infection through the skin. Proteolytic activity necessary for the virus to enter cells may be enhanced
in tissue exposed to S. aureus as well as by the bacteria’s own secreted proteases. Finally, S. aureus carriage could be a risk
factor for the development of secondary bacterial pneumonia during primary COVID-19 infection. In order to avoid infection
and severe disease outcomes, it is important for those suspected of having diabetes to maintain strict glycemic control andtake measures to avoid exposure to the virus.

KEY WORDS: COVID-19, SARS-CoV-2, diabetes mellitus, Staphylococcus aureus, biofilm, pneumonia,
		glycative stress, advanced glycation endproducts (AGEs)

Introduction
It is said that people with diabetes, a representative
condition with high glycative stress, are more likely to havecoronavirus induced (COVID-19) pneumonia, and coronavirus
pneumonia is more likely to become severe 1-4). Although it isa subject that still remains unclear, we would like to present a
literature review of this issue.
Aichi Medical University conducted a large-scale survey(45,000 cases or more) on the causes of death in diabetic
patients. As a result, malignant tumors were observed in
38 % of cases, followed by 17% of cases involving infectious
diseases such as pneumonia 5). It has been reported thatpeople with diabetes are about 1.8 times more likely to havepneumonia than people without it. Infections as complicationsof diabetes investigated in Japan consisted of pneumonia(respiratory infection): about 40 %, urinary tract infection:
25%, skin and soft tissue infection: 20 %.

There are many factors involved in cases when it comesto diabetes. The situation is quite different for people who areproperly treated and have good glycemic control, those whoare being treated but have insufficient glycemic control, andthose who are left untreated for hyperglycemia. Naturally,
people with severe hyperglycemia have a higher risk ofpneumonia and a higher mortality rate 6). Therefore, diabetics
should have strict glycemic control, avoid postprandial
hyperglycemia, and carefully and voluntarily take precautions
to avoid infection.

Reduced immune function
Why are people with diabetes prone to infections? The
human body is constantly attacked by viruses and bacteriathat try to enter it, so it has a sophisticated defense mechanism
against infection. However, diabetes has weakened the defense
mechanism against infection.

Contact Address: Professor Yoshikazu Yonei, MD, PhD
Anti-Aging Medical Research Center/Glycative Stress Research Center,
Graduate School of Life and Medical Sciences, Doshisha University
1-3, Tatara Miyakodani, Kyotanabe, Kyoto, 610-0394 Japan
TEL / FAX: +81-774 -65- 6394 e-mail: yyonei@mail.doshisha.ac.jp
Co-authors: Haasbroek K, cygd2001@mail4.doshisha.ac.jp;
Yagi M, myagi@mail.doshisha.ac.jp

Glycative Stress Research 2020; 7 ( 3) : 232- 239(c) Society for Glycative Stress Research_ 232 _Glycative Stress Research

Immune function is the most important defense
mechanism. Various types of immune cells cooperate witheach other while fighting against external enemies, i.e.,bacteria, viruses, and cancer cells. When glycative stress,
i.e., diabetes, becomes strong, individual immune cells areaffected and immune function declines.
There are two main mechanisms by which the functionof immune cells is reduced by glycative stress (Fig. 1). The
first pathway is mitochondrial function decline. The second
is a pathway that causes endoplasmic reticulum (ER) stressin which advanced glycation endproducts (AGEs) produced
by glycative stress are taken up into the cell, the burdenof foreign matter processing increases, and cell function
declines.
First mechanism: Hyperglycemia and AGEs severely
damage mitochondria. Inside the mitochondria there is asystem of energy production called the TCA cycle. When the
TCA cycle is impaired, energy production is reduced and thecells become impaired. In this state, fumaric acid increases
and reacts with protein to produce succinylated protein (alsocalled 2SC protein) 7). When an important protein such as an
enzyme is denatured by 2SC modification, the function ofthat enzyme is impaired. As a result, the functions associatedwith that enzyme are diminished.
Second mechanism: AGEs are taken into cells throughcell surface scavenger receptors 8, 9). A scavenger is a cleaner,
and it is a receptor for processing foreign substances, in thiscase AGEs. When AGEs increase in cells, the burden of
foreign matter processing increases and cell function declines
10). This condition is called ER stress. The ER is an organelle
in the cell called the endoplasmic reticulum, where proteinsare processed and synthesized.
Glycative stress impairs the function of immune cells.
White blood cells that compose immune cells include
neutrophils, macrophages (cells in which monocytes have
evolved), lymphocytes, and natural killer (NK) cells. AGEs
impede the proper functioning of these cells in various ways.

“ Decreased phagocytosis ”
When viruses and bacteria enter the body, neutrophils
and macrophages take them into cells and degrade them. Thisis called phagocytosis. If this function declines, the ability
to kill pathogens will be weakened. Phagocytic activity issignificantly decreased in individuals with diabetes, andAGEs directly suppress phagocytosis in macrophages 11).
Further research demonstrates that incorporation of AGEs
into macrophages causes apoptosis 12), reducing the number of
viable macrophages during high glycative stress.

“Reduced chemotaxis of neutrophils”
Chemotaxis is the function of moving toward an
inflammatory site. Neutrophils are characterized in that they

T2DM, etc.

Glycative
stress

AGEs
Scavenger
receptor

RAGE

Hyperglycemia

Mitochondria
dysfunction

AGEs↑

TCA disorder
Fumarate↑
Succinylation↑

ER stress↑

Succinylated
protein

Cytokineproduction

Inflammatory cytokine
releaseCytokine storm↑

Immune cell function↓
Phagocytosis↓
Chemotaxi↓
Immunoglobulin production↓
Cooperation↓

Fig. 1. Glycative stress and the function of immune cells.

AGEs, advanced glycation endproducts; RAGE, receptor for AGEs; T2DM, type 2 diabetes mellitus; TCA,
tricarboxylic acid; ER, endoplasmic reticulum.

_ 233 _Glycative Stress and COVID-19 Infection

first gather at the site of pathogen entry and inflammation andplay a role in the initial response during infection. Neutrophils
exposed to diabetic donor serum show reduced migrationin response to chemical signals 13), and activation of RAGE
(receptor for AGEs) by AGEs increases binding to collagen,reducing chemotaxis in the extracellular matrix 14). When thisfunction declines, the cell migration speed slows down andthe immune response is delayed.

“ Lower immunoglobulin production”
Antibodies are proteins, called immunoglobulin, thatbind to bacteria and viruses and work to defeat foreign
enemies. Antibodies are produced by B lymphocytes. As otherfactors, neutrophils and NK cells produce free radicals andcytokines, i.e. TNF-α, thus exert bactericidal and viricidal
action. When glycative stress is high, production and secretionof these substances are reduced 15-18), and the ability to kill
pathogens is weakened.

“ Reduced cooperation ”
Immune cells play their role in cooperation with eachother. The cells signal and detect each other, sometimes
enhancing bactericidal ability and sometimes controllinginflammation.
However, if glycative stress is strong, the signal response
will be impaired and the cooperation will be hindered. As aresult, the defensive power against viruses and bacteria andbactericidal ability is reduced, so that infections are more
likely to occur.
When AGEs bind to the RAGE, it increases the
production of cytokines that cause inf lammation.
Inflammatory cytokines generally act competitively withinsulin, which raises blood sugar levels and further impairs
blood sugar control. In addition, inflammatory cytokines may
be over secreted. This is called a cytokine storm 19) and is amajor factor in the severity of new coronavirus pneumonia.

Effects on skin and mucous membrane
defense mechanisms

The transmission route of COVID-19 is mainly droplet
infection and contact infection. In the case of droplet
infection, patients are infected by inhaling the droplets froma cough and attaching them to the bronchial mucosa, or byattaching the droplets directly to the mucous membranesof their nose or eyes. In the case of contact infection, after
contacting the patient or attaching to the skin of the handthrough a doorknob or food containing a pathogen, it istransmitted through the eyes, nose or mucous membrane ofthe oral cavity. Namely, COVID-19 has the characteristicthat it easily penetrates through mucous membranes. Amongthem, the oral mucous membrane is the most susceptible toglycative stress.
When blood sugar level rises, the sugar concentration insaliva rises (saliva hyperglycemia). Therefore, in people withdiabetes, periodontal disease bacteria and caries (cavities)
may grow, resulting in poor oral hygiene and high prevalenceof periodontal disease and caries. These pathogens reproduce
by forming a film called biofilm, in which members of thegroup gather and share nutrient sources with each other.
In this way, they protect themselves from the enemy
bacteria and escape the phagocytosis of white blood cells
and immunological attacks, i.e., antibodies, cytokines. There
are numerous biofilms on plaque, which can cause aspiration
pneumonia. The association between biofilms and COVID-19
is unknown at this time, but we suspect that there may be a
relationship. Maintaining oral hygiene is important for theprevention of new coronavirus pneumonia.

SARS-CoV-2 Mechanism of Infection
There is a molecular mechanism on the cell surface thatallows COVID-19 to enter efficiently. The virus targets the"ACE2 (angiotensin-converting enzyme 2)" receptor as the"entrance" to cells, and utilizes "TMPRSS2" and/or "furin",which are proteolytic enzymes 20). The viral spike protein binds
to ACE2, then TMPRSS2 and furin on the cell membranecleave the protein at the appropriate position, supporting thefusion of viral and cellular membranes 21). The virus invades
the cell and injects genetic material, RNA. The cell will
become a "factory" and will be able to self-replicate large
amounts of the virus. SARS-CoV-2 possesses a novel 4 aminoacid insert in its spike protein, allowing it to be primed more
readily and by a wider variety of host proteases than SARSCoV-1 22). In addition to furin and TMPRSS2, other proteases
such as PC1, trypsin, TTSP matriptase, and cathepsins B andL have also demonstrated the ability to activate the viral spike
protein.

“ACE2 Expression ”
Paradoxically, ACE2 expression is seemingly reduced inlong-term diabetes based on murine models 23) (cardiovascular
ACE2) and human studies 24) (renal ACE2). However, diabetic
patients who are undergoing treatment with ACE inhibitors
show the opposite effect: while ACE inhibitors downregulate
expression of ACE1, this consequently results in upregulationof ACE2 25-27). Despite this potential risk, a study of actual
cases involving ACE inhibitor use demonstrated decreased
mortality in COVID-19 patients taking the medication 28). Theinteraction of the systems of ACE2 expression, diabetes, and
COVID-19 are complex and difficult to predict.

Glycative stress also affects the skin's
defense mechanism.

COVID-19 is not transmitted through healthy skin.
However, if you have diabetes, many people will be awareof symptoms like rough skin, dry skin, and itching. Further
disease progress can increase the likelihood of skininfections such as ringworm (athlete's foot) and candidiasis,and sometimes lead to skin erosion. In such areas, the virus
can also penetrate through the skin. It is said that infection_ 23 4 _Glycative Stress Researchis particularly likely to occur on areas of thin skin suchas the lips and pubic region. Excessive hand washing, useof alcohol sanitizers, and extended use of PPE (personal
protective equipment, e.g. masks, gloves) due to the current
pandemic are causing an increase in skin damage anddryness, further contributing to skin vulnerability 29).
In our laboratory, we pay attention to the skin-resident
microflora and study the changes due to aging and theeffects of glycative stress. Staphylococcus epidermidis andStaphylococcus aureus reside on the skin in significant
quantity. The former is also called "beautiful skin bacteria,"
a potential probiotic which is common among young
people, but decreases with age and diabetes. Conversely, inolder people and diabetics, S. aureus increases and biofilm
formation becomes more noticeable. In our research (currently
preparing for publication) we have come to know that AGEs
promote biofilm formation. AGEs formed from glucose andkeratin cause a roughly 10-fold increase in biofilm formationcompared to controls in S. aureus at dosages of 0.1~1 mg/mLof keratin. The skin of diabetics, with high AGE content, isideal for the formation of S. aureus biofilms. When combinedwith skin lesions, an abundance of S. aureus and its biofilms
may further break down vulnerable skin, slow wound healing,damage the skin’s barrier function, and cause inflammation.
In addition to the skin, S. aureus also inhabits the nasal cavity,
which is the primary reservoir for the bacteria on the body of
persistent carriers.
The skin itself is rich in RNA and DNA degrading

enzymes 30, 31), which may degrade viral RNA and reduce
its survival time on the skin surface. Bacterial biofilms are
partially composed of extracellular DNA which forms a
substantial part of the biofilm matrix 32), and are broken down
by ribonucleases 33-35); these enzymes will be diminished in
the environment of a stable biofilm, which may also protect
SARS-CoV-2 from degradation on bare skin, allowing it topersist for longer on the skin surface.
Considering these factors, we reviewed the literature forother potential mechanisms that could exacerbate COVID-19
in the case of S. aureus carriage. We found that the presenceof S. aureus and its proteases could play a potential role inincreasing susceptibility to SARS-CoV-2. There are two main
pathways for S. aureus to promote susceptibility to COVID-19:
modulating host protease activity, and by priming the virus
with its own bacterial proteases ( Fig. 2).
Exposure to S. aureus factors triggers an increase inserine protease activity in human keratinocytes. Trypsin
and the KLK family of proteases expression in humankeratinocytes was shown to increase in vitro, and in vivo
murine models also showed increased serine protease activity
in the skin after exposure to S. aureus 36). Another study of
S. aureus in atopic dermatitis skin lesions revealed that
S. aureus strains colonizing lesions demonstrated increased
proteolytic activity when compared to reference strains 37).
Tissues experiencing this effect would produce more hostprotease, increasing viral fusion and infection rate. While
there does not appear to be any data on the host protease

Diabetes, etc.

Glycative
Stress

SARS-CoV-2

Glucose-Keratin

Aging
Biofilm

AGEs
Prolonged
Survival/Buildup

Probiotic Flora (“Beautiful skin bacteria”）

Pathogenic Flora
Roughness
Dryness
Itching

Stratum Corneum

Easier Invasion

Epidermis

Increased Proteolytic Activity
Inflammation

Stratum Basale
DermisFig. 2. Glycative stress and the defense mechanism in skin.
AGEs, advanced glycation endproducts.

_ 235 _Glycative Stress and COVID-19 Infection

response in the nasal mucosa, the presence of S. aureus andits secreted serine proteases in the nose have been shown tohave an immunomodulatory effect on nasal epithelia cells,
increasing cytokine production and causing inflammation 38).
Although it seems that there are not yet any studies
examining the capacity for bacterial proteases to interact
with the SARS-CoV-2 viral spike protein, S. aureus relies ona suite of secreted proteases for its nutrient metabolism aswell as protection against host defenses 39). These include twocysteine proteases (staphopain A and B), a metalloprotease(auerolysin), a serine protease (V8), and six serine proteaselike proteins (SplA – SplF). It is possible that some of these
may have overlapping specificity with the human proteases
previously noted to interact with SARS-CoV-2. Additionally,
S. aureus also secretes proteins that specifically inhibit
neutrophil proteases 40), impeding the ability of the immune
system to clear invading pathogens.
Here we have collected recent findings on COVID-19
and skin and mucosal membranes.

S. aureus secondary infection during
COVID-19

S. aureus carriage is already a potential risk factor
in hospital settings under normal circumstances, being
associated with increased incidence of surgery site infections
41, 42), and nosocomial spread of MRSA is a relatively common
occurrence. Presence of S. aureus is also a risk factor for coinfection with other viral infections; the S. aureus protein
lipase 1 has been found to increase replication of the
Influenza A virus 43), and Influenza can also trigger virulencein commensal nasal S. aureus 44), leading to secondary
pulmonary infection and bacterial pneumonia. Co-infection is
also a serious concern for COVID-19, and similar processes
may be a generalizable factor. A thorough meta analysis of
COVID-19 patients 45) reveals that 7 % of hospitalized patients(and 14% of ICU patients) had confirmed cases of bacterial
co-infection, and were at significantly higher risk of death. In
some cases, up to 50 % of non-survivors of COVID-19 havepresented with co-infection 46). Elevated body temperaturesfrom fever promote the dissolution of S. aureus biofilms 44):
if S. aureus biofilms are present in the nasal cavity, highconcentrations of S. aureus cells may be aspirated into
the lungs, leading to secondary infection. A fatal case of
secondary lung infection by S. aureus during COVID -19 has
been reported 4 7).

COVID-19 skin infection

Some hospital dermatology departments have issued
reports regarding their concerns of increased vulnerability
for their patients who could more easily contract the diseaseduring hospital visits 29, 48). COVID-19 infection of the skin istheoretically possible. ACE2, while highly expressed in thelungs and nasal mucosa, is expressed throughout many tissues
in the body, including the skin 49, 50). Increasingly there arealso reports of skin rashes as an early COVID-19 symptom. A
survey through a monitoring application (n = 336,847) reports
8.8% incidence of skin rash in positive cases, and a separate

survey of COVID-19 patients (n = 11,546) found that 17% of
patients experienced a rash as their first symptom, and 21%
as their only symptom 51). While the pathogenic mechanismof theses rashes/lesions is still unclear, it is hypothesized thatthey may occur due to a hyperactive immune response and/or vascular damage 52): not necessarily due to infection of theskin itself. Other case studies have noted the formation ofvesicular rashes in some patients 53-55), which form from viral
replication in the skin in other disease systems (e.g., Herpes
simplex, poxviruses, Varicella zoster). However, researchers
were unable to detect viral RNA in the fluid of these vesicles 53)(although they note the apparent unreliability of skin PCR
and question whether low viral load prevented detectionof the virus). Nevertheless, infection through the skin is a
plausible concern, in addition to the more vulnerable mucosal
membranes.
While the risk of infection through skin lesions is
unclear, it is clear that mucous membranes are a likely entry
point for the virus during infection, especially the nasal
epithelia where ACE2 is highly expressed 56). Both in the noseand on the skin S. aureus proteases have the opportunity tocontribute to the virulence of SARS-CoV-2. Outside of thenose, S. aureus is most highly abundant on the hands, chest,
and skin near sebaceous glands and mucous membranes. In
either case, S. aureus may interact with host tissues and thevirus in ways that could increase the susceptibility to andseverity of infection.

Reduced blood flow and microcirculatory
disturbances

Hyperglycemia causes damage to peripheral nerves.
Nerves that feel pain and itching are also damaged, so it
may be difficult for symptoms to appear and furthermore
becoming difficult to notice skin lesions. These unnoticed
skin lesions also provide vulnerable targets for S. aureus
colonization and infection.
Also, in hyperglycemia, the blood flow through the thinblood vessels of the skin is impaired. In such a state, oxygenand nutrients are not sufficiently distributed, immune cells
are less likely to collect at the infected site, and the functionof immune cells is reduced. Therefore, pathogens are more
likely cause infection.
States with high glycative stress, i.e., obesity 57),
glucose intolerance, diabetes 58), not only increase the riskof coronavirus infection, but also increases the frequency ofthrombus formation. Thrombus formation becomes a factor
of disease severity and increases the mortality rate 59- 61).
An important phenomenon in the process in which glycative
stress influences thrombus formation is vascular endothelial
injury. We have pointed out the possibility that postprandial
hyperglycemia (glucose spikes) increases linear glucose andfructose containing exposed aldehyde groups which graduallyreact with saccharides in blood vessels and sugar chains oncell membranes to simultaneously produce multiple aldehydes(aldehyde spark) 62). Aldehydes have high reactivity not onlywith sugar chains but also with proteins, thus inducing
extensive damage in the vascular endothelium, where rolling_ 23 6 _Glycative Stress Researchand sticking of leukocytes appear in advance at the lesion
site, and eventually a series of microcirculatory disorders
leads to leukocyte adherence, emigration in venules, rouleauxformation of red blood cells, and finally causing platelet
aggregation and thrombus formation. We have been studying
the microcirculation using in vivo microscopy and observedthat similar phenomena in the gastric mucosal are caused byadministration of ethanol or indomethacin 63, 64). It is importantto prevent endothelial damage due to glycative stress asmuch as possible in order to prevent thrombosis, a serious
complication of COVID-19 infection.

Conclusions
Again, the SARS-CoV-2 virus first attaches to theskin of the fingers, and then enters the body via the bulbar
conjunctiva, the mucous membranes of the oral cavity andbronchi, by rubbing the eyes and touching the lips. Whether
or not an infection is then triggered depends on whether the

immune system can eliminate the virus. When glycative stressis strong, the defense mechanisms of the skin and mucous
membranes are weakened and immune function is impaired,
so new coronavirus pneumonia more easily develops.
Colonization of the body by poteintially pathogenic florasuch as S. aureus, increasing with glycative stress, may be arisk factor for co-infection. The presence of bacterial biofilms
may reduce skin barrier function and modulate proteolytic
activity such that viral infection is more liekly to occur.
People with diabetes (including suspicion of having
diabetes) should have strict glycemic control, and people
without diabetes should reduce postprandial hyperglycemia.

Conflict of Interest Statement
The authors claim no conflict of interest in this study.

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