CONTRIBUTION OF TOLL-LIKE RECEPTORS TO THE IMMUNE RESPONSE IN UPPER RESPIRATORY TRACT INFECTIONS

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CONTRIBUTION OF TOLL-LIKE RECEPTORS TO THE IMMUNE RESPONSE IN

UPPER RESPIRATORY TRACT INFECTIONS

DSc

I.Yu. Mamatova,

Phd

O.K.Djalalova

Andijan state medical institute

Abstract:

Upper respiratory tract infections (URTIs) are among the most common infectious

diseases worldwide, caused primarily by viruses and, less frequently, by bacteria. Toll-like

receptors (TLRs), as key components of the innate immune system, play a central role in

recognizing pathogen-associated molecular patterns (PAMPs) and initiating immune responses

in the respiratory epithelium. This article reviews the expression and function of TLRs in the

upper respiratory tract, their involvement in pathogen detection, and the consequences of

dysregulated TLR signaling. Understanding TLR-mediated mechanisms in URTIs may aid in

developing novel immunomodulatory therapies.

1. Introduction

The upper respiratory tract serves as the primary entry point for a variety of airborne pathogens,

including viruses such as rhinoviruses, influenza viruses, and coronaviruses, as well as bacteria

like

Streptococcus pneumoniae

. Toll-like receptors (TLRs) are essential pattern recognition

receptors (PRRs) that detect microbial components and trigger innate immune responses (Kawai

& Akira, 2010). In the respiratory mucosa, epithelial cells and immune cells express TLRs that

contribute to early pathogen recognition and shaping of adaptive immunity (Bals & Hiemstra,

2004).

2. Expression and Localization of TLRs in the Upper Respiratory Tract

Different TLRs are differentially expressed in various cell types of the upper airway, including

nasal epithelial cells, macrophages, and dendritic cells. TLR3, TLR7, and TLR8 are primarily

located in endosomes and recognize viral RNA, while TLR2 and TLR4, expressed on the cell

surface, detect bacterial lipoproteins and lipopolysaccharides, respectively (Kaisho & Akira,

2006). For instance, nasal epithelial cells express high levels of TLR3 and TLR7, which are

essential for recognizing influenza and rhinoviral infections (Hajjar et al., 2002).

The upper respiratory tract (URT), which includes the nasal passages, nasopharynx, and

oropharynx, is the first line of defense against inhaled pathogens.

Toll-like receptors (TLRs)

are expressed by various cell types in the URT, including epithelial cells, dendritic cells (DCs),

macrophages, and endothelial cells. Their expression patterns and cellular localization are

essential for initiating immune responses against both bacterial and viral pathogens.

TLR Expression in Nasal and Respiratory Epithelium

The

respiratory epithelium

, which forms the mucosal barrier of the URT, expresses several

TLRs, with the highest expression levels observed for

TLR2

,

TLR3

,

TLR4

, and

TLR5

. These

TLRs are crucial for detecting pathogen-associated molecular patterns (PAMPs) such as

lipoproteins, lipopolysaccharides, flagellin, and viral RNA.



TLR2

is highly expressed on the surface of nasal epithelial cells, particularly those in the

upper respiratory tract. It recognizes components of

Gram-positive bacteria

(e.g.,

Staphylococcus aureus

,

Streptococcus pneumoniae

) and activates inflammatory pathways

(Toshchakov et al., 2002).



TLR3

, located predominantly in endosomal membranes, recognizes

double-stranded

RNA (dsRNA)

produced by many viruses, including

influenza

and

rhinoviruses

. It is

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expressed in epithelial cells and dendritic cells of the URT (Alexopoulou et al., 2001).



TLR4

is expressed on both the apical and basolateral surfaces of respiratory epithelial

cells, where it plays a key role in detecting

lipopolysaccharides (LPS)

from

Gram-

negative bacteria

like

Haemophilus influenzae

(Hoshino et al., 2002). It can also

recognize viral glycoproteins, such as the

RSV fusion protein

(Kurt-Jones et al., 2000).



TLR5

, present on the apical surface of airway epithelial cells, is primarily involved in

recognizing

flagellin

, a component of bacterial flagella. This TLR is involved in

detecting motile bacteria, such as

Pseudomonas aeruginosa

(Hayashi et al., 2001).

TLR Expression in Dendritic Cells and Macrophages

Dendritic cells (DCs) are central to the immune response in the URT and play a critical role in

TLR-mediated pathogen detection.

Plasmacytoid dendritic cells (pDCs)

, which are abundant in

the nasal mucosa, express

TLR7

and

TLR9

and are crucial for the detection of

single-stranded

RNA (ssRNA)

viruses like

influenza

and

rhinovirus

(Lund et al., 2004). These pDCs produce

type I interferons (IFNs), which are essential for limiting viral replication.

Macrophages

also express multiple TLRs, including

TLR2

,

TLR4

,

TLR5

, and

TLR9

. They

play a key role in clearing pathogens and promoting inflammation in response to infection. These

cells are involved in both

direct pathogen killing

and the

activation of adaptive immunity

via

the secretion of cytokines such as TNF-α, IL-6, and IL-12 (Toshchakov et al., 2002).

Localization of TLRs in Upper Respiratory Tract Tissues

The localization of TLRs in the URT is important for the initial detection of pathogens that are

inhaled. TLRs are localized not only in epithelial cells but also in immune cells in the

nasal

mucosa

,

sinuses

, and

pharyngeal tissues

. This ensures that TLRs are in close proximity to

pathogens entering the div through the airways.



In the

nasal mucosa

, TLR2, TLR3, TLR4, and TLR5 are expressed on the apical surface

of epithelial cells, which are the first line of defense against airborne pathogens. These

receptors are particularly important for detecting

bacterial pathogens

and initiating the

innate immune response.



Dendritic cells

in the mucosa express

TLR7

and

TLR9

in endosomal compartments,

where they detect

viral RNA and DNA

. They migrate to local lymph nodes to activate

adaptive immune responses (Lund et al., 2004).

In the

sinuses

and

pharyngeal tissues

, both epithelial cells and immune cells, including

macrophages

and

neutrophils

, express TLRs. These tissues are critical sites for pathogen

recognition in

sinusitis

and

pharyngitis

, conditions often associated with both bacterial and viral

infections.

Regulation of TLR Expression in the URT

The expression of TLRs in the URT is

regulated by environmental factors

such as infection,

allergens, and inflammatory cytokines. For example,

interleukin-1β (IL-1β)

and

tumor

necrosis factor-α (TNF-α)

, which are produced during infection, can upregulate the expression

of TLRs on respiratory epithelial cells, enhancing the sensitivity to pathogens (Bazzoni et al.,

1999). In contrast, chronic exposure to allergens or pollutants can alter the expression of TLRs

and may contribute to conditions like

asthma

or

chronic rhinosinusitis

(Tsoyi et al., 2011).

In

chronic respiratory diseases

, such as

asthma

and

chronic obstructive pulmonary disease

(COPD)

, TLR expression can become dysregulated. Overexpression of certain TLRs,

particularly TLR2 and TLR4, has been observed in

smokers

and individuals with

COPD

, which

may contribute to the

chronic inflammation

seen in these conditions (Tsoyi et al., 2011).

3. TLRs and Viral Upper Respiratory Tract Infections

Viral infections such as influenza, RSV (respiratory syncytial virus), and SARS-CoV-2 are major

causes of URTIs. TLR3 recognizes double-stranded RNA, a viral replication intermediate, and

activates interferon regulatory factors (IRF3/7), leading to the production of type I interferons

(IFN-α/β) (Kurt-Jones et al., 2000). TLR7 and TLR8 recognize single-stranded RNA from

viruses like RSV and SARS-CoV-2 and similarly trigger antiviral pathways (Diebold et al.,

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2004). These responses help limit viral replication but can also cause excessive inflammation if

not properly regulated.

Toll-like receptors (TLRs) are pivotal for initiating immune responses against viruses that infect

the upper respiratory tract (URT), including

influenza viruses

,

respiratory syncytial virus

(RSV)

,

rhinoviruses

, and

coronaviruses

(including SARS-CoV-2). Viral components such as

single-stranded RNA (ssRNA)

,

double-stranded RNA (dsRNA)

, and

viral proteins

are

recognized by specific TLRs, triggering antiviral signaling pathways that culminate in the

production of

type I interferons (IFNs)

and

proinflammatory cytokines

(Akira et al., 2006).

TLR3: Sensing Double-Stranded RNA

TLR3

, expressed on endosomal membranes of epithelial cells, dendritic cells (especially

CD103⁺ respiratory DCs), and macrophages, recognizes

viral dsRNA

, an intermediate product

during viral replication (Alexopoulou et al., 2001). Upon activation, TLR3 recruits the adaptor

protein

TRIF

, leading to the induction of

IFN-β

,

IL-6

, and

TNF-α

, crucial for controlling

infections such as

influenza A

and

rhinovirus

(Le Goffic et al., 2006). In murine models,

TLR3-deficient mice exhibit reduced IFN responses and impaired viral clearance (Le Goffic et

al., 2006).

TLR7 and TLR8: Detecting Single-Stranded Viral RNA

TLR7

and

TLR8

, primarily found in

plasmacytoid dendritic cells (pDCs)

and monocytes, are

responsible for recognizing

ssRNA

from viruses such as

influenza

,

RSV

, and

coronaviruses

(Diebold et al., 2004). These TLRs signal via the

MyD88-dependent pathway

, resulting in

strong production of

type I IFNs (IFN-α/β)

, which establish an antiviral state and modulate

adaptive immunity (Kawai & Akira, 2010). Notably, pDCs are among the most potent producers

of type I IFNs in response to influenza infection, largely via TLR7-mediated sensing (Lund et al.,

2004).

TLR9: Recognizing DNA Viruses

Though less common in URT infections,

TLR9

detects

unmethylated CpG DNA

from

DNA

viruses

such as

adenoviruses

and

herpesviruses

(Hemmi et al., 2000). TLR9 activation

contributes to IFN production and can modulate the outcome of co-infections or secondary

bacterial infections during viral URT illness (Kumagai et al., 2007).

TLR4 and TLR2: Non-Canonical Viral Sensing

While primarily involved in bacterial recognition,

TLR4

and

TLR2

also participate in immune

responses to certain viral proteins. For example,

RSV fusion (F) protein

activates

TLR4

,

enhancing cytokine production and neutrophil recruitment (Kurt-Jones et al., 2000). Similarly,

TLR2

can detect

viral envelope proteins

, contributing to inflammatory responses in

rhinovirus

and

coronavirus

infections (Triantafilou et al., 2004; Choudhury & Mukherjee, 2020).

Clinical Implications

Inappropriate or excessive TLR activation during viral URT infections can contribute to

immunopathology

. For instance,

overactive TLR3 or TLR7 signaling

has been implicated in

tissue damage during severe influenza and COVID-19 infections due to exaggerated cytokine

release (Totura et al., 2015; van der Made et al., 2020). Conversely,

loss-of-function mutations

in TLR7

are associated with

severe COVID-19 in young males

, underlining its importance in

early antiviral defense (van der Made et al., 2020).

TLR-targeted therapies, such as

TLR7/8 agonists

, are under investigation for their

adjuvant

potential in intranasal vaccines

, enhancing mucosal immunity against viruses like influenza

and SARS-CoV-2 (Kasturi et al., 2011). On the other hand,

TLR antagonists

may help

dampen

hyperinflammatory responses

in cases of cytokine storm syndromes.

4. TLRs and Bacterial Infections of the Upper Respiratory Tract

TLR2 and TLR4 are primarily involved in detecting bacterial components. TLR2 recognizes

lipoteichoic acid from gram-positive bacteria like

Streptococcus pneumoniae

, while TLR4 binds

to lipopolysaccharides from gram-negative pathogens (Takeuchi et al., 1999). The activation of

these receptors leads to NF-κB-dependent transcription of pro-inflammatory cytokines (IL-1β,

TNF-α), facilitating neutrophil recruitment and bacterial clearance (Cohen et al., 2000).

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The upper respiratory tract (URT) is frequently exposed to bacterial pathogens such as

Streptococcus pneumoniae

,

Haemophilus influenzae

,

Moraxella catarrhalis

, and

Staphylococcus

aureus

. The innate immune system relies heavily on Toll-like receptors (TLRs) for early

recognition and response to these bacterial invaders. Among the most relevant TLRs in bacterial

URT infections are TLR2, TLR4, TLR5, and TLR9.

TLR2

plays a crucial role in recognizing components of Gram-positive bacteria, such as

lipoteichoic acid (LTA), peptidoglycan, and bacterial lipoproteins. It often forms heterodimers

with TLR1 or TLR6 to expand its range of ligand recognition (Takeuchi et al., 2001). For

instance, in infections with

S. pneumoniae

, TLR2 activation leads to the release of inflammatory

cytokines like TNF-α, IL-6, and IL-1β, which recruit neutrophils and macrophages to the

infection site (Zhang et al., 2007).

TLR4

, primarily associated with Gram-negative bacteria, recognizes lipopolysaccharide (LPS)

from organisms such as

Haemophilus influenzae

. It signals through both MyD88-dependent and

TRIF-dependent pathways, leading to the production of pro-inflammatory cytokines and type I

interferons (Beutler, 2000; Hoshino et al., 2002). Notably, TLR4 activation is crucial for defense

against

H. influenzae

-induced otitis media and sinusitis (Leichtle et al., 2009).

TLR5

detects bacterial flagellin, a structural component of motile bacteria, including

Pseudomonas aeruginosa

, which can colonize the URT, especially in immunocompromised

individuals. TLR5 is expressed on epithelial cells lining the nasal passages and sinuses and

contributes to mucosal immune activation and neutrophil recruitment (Hayashi et al., 2001).

TLR9

, located in endosomes, recognizes unmethylated CpG motifs in bacterial DNA,

particularly from Gram-positive bacteria like

S. aureus

. Activation of TLR9 contributes to the

production of interferon-α and the modulation of B-cell responses (Hemmi et al., 2000).

In addition to pathogen recognition, TLRs influence the

severity and duration

of bacterial

infections. For example, impaired TLR2 or TLR4 signaling in knockout mice results in delayed

bacterial clearance and prolonged inflammation during

S. pneumoniae

or

H. influenzae

infections

(Albiger et al., 2005; Melhus & Ryan, 2000). Moreover, excessive TLR activation can contribute

to tissue damage, indicating a need for tightly regulated signaling.

Furthermore, some bacteria have evolved mechanisms to

evade or manipulate TLR signaling

.

S. pneumoniae

, for instance, can alter its cell wall components to reduce TLR2 activation, while

H. influenzae

modifies its LPS structure to escape TLR4 detection (Weiser et al., 2018).

Understanding the role of TLRs in bacterial URT infections has

clinical implications

. For

instance, TLR agonists (e.g., synthetic lipopeptides targeting TLR2) are being studied as vaccine

adjuvants to boost mucosal immunity. Conversely, TLR antagonists may be considered to

manage excessive inflammation in chronic conditions like recurrent sinusitis (de Vos et al.,

2009).

5. Crosstalk and Regulation of TLR Signaling in URTIs

TLR activation is tightly regulated to prevent tissue damage from excessive inflammation.

Negative regulators such as SIGIRR and IRAK-M help dampen TLR signaling after pathogen

clearance (Kobayashi et al., 2002). Moreover, crosstalk among TLRs and other PRRs (e.g., RIG-

I) modulates the intensity and specificity of the immune response. Dysregulation of TLR

signaling is associated with chronic rhinosinusitis and increased susceptibility to secondary

infections (Lane et al., 2006).

6. Clinical Implications and Therapeutic Potential

Targeting TLRs offers a promising strategy in managing URTIs. TLR agonists are being

explored as adjuvants in intranasal vaccines, enhancing mucosal immunity (Matsuo et al., 2010).

Conversely, TLR antagonists may help mitigate severe inflammatory responses in viral

infections, such as during cytokine storms in COVID-19 (van der Made et al., 2020).

Toll-like receptors (TLRs) are fundamental in the detection of pathogens in the upper respiratory

tract (URT), and their involvement in both protective immune responses and immunopathology

has significant clinical implications. While TLRs provide critical early responses to viral and

bacterial infections, dysregulation of their signaling pathways can contribute to excessive

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inflammation, tissue damage, and chronic respiratory diseases. Understanding the roles of TLRs

in these infections opens avenues for novel therapeutic strategies aimed at either enhancing TLR

responses to clear infections more efficiently or modulating their activity to prevent tissue

damage and inflammation.

1. TLR Agonists in Vaccine Development

TLR agonists have been explored as potential

adjuvants

in vaccines, particularly those aimed at

protecting against respiratory infections such as

influenza

,

RSV

, and

SARS-CoV-2

. These

agonists activate innate immune responses and enhance the

mucosal immunity

in the respiratory

tract.

TLR7/8

agonists, for example, have been shown to improve

immunogenicity

and

protection

in preclinical models of respiratory infections (Kasturi et al., 2011). TLR-based

vaccine adjuvants can stimulate the production of

type I interferons (IFNs)

and

cytokines

,

which are essential for robust antiviral immunity and long-lasting protection.

A major advantage of TLR agonist-based vaccines is their ability to activate both the

innate

and

adaptive immune responses

. The TLR7/8 agonist

resiquimod

, for example, has demonstrated

efficacy in enhancing immune responses when used alongside vaccines for

influenza

(Poo et al.,

2015). Furthermore,

TLR9 agonists

have shown potential in the development of vaccines for

DNA viruses

such as

adenovirus

and

herpes simplex virus (HSV)

(Tregoning et al., 2018).

2. Targeting TLRs to Control Inflammation in Viral Respiratory Infections

While TLRs are crucial for initiating the immune response to respiratory pathogens, their

activation can sometimes lead to

excessive inflammation

, contributing to

immunopathology

.

For example, excessive activation of

TLR3

during

influenza

infection has been linked to

acute

lung injury

and

cytokine storms

(Le Goffic et al., 2006). Similarly,

TLR7

activation has been

implicated in

severe COVID-19

, where hyperactivation of the immune response leads to

acute

respiratory distress syndrome (ARDS)

and

cytokine release syndrome

(van der Made et al.,

2020).

Therefore,

TLR antagonists

or

modulators

may be beneficial in treating conditions with

excessive immune activation

.

TLR4 antagonists

, for example, have been shown to reduce

inflammation and tissue damage in animal models of

bacterial pneumonia

(Tiwari et al., 2014).

TLR2 antagonists

may be useful in preventing

chronic inflammation

associated with diseases

like

asthma

and

chronic rhinosinusitis

(Tsoyi et al., 2011).

3. Modulation of TLR Responses in Chronic Respiratory Diseases

Chronic respiratory diseases such as

asthma

,

chronic obstructive pulmonary disease (COPD)

,

and

chronic rhinosinusitis

are often characterized by persistent inflammation in the respiratory

tract.

Dysregulation of TLR signaling

plays a key role in the chronicity of these conditions. For

example,

TLR2

and

TLR4

are upregulated in the airways of individuals with

COPD

(Tsoyi et

al., 2011).

TLR5

has also been implicated in

sinusitis

, where its activation promotes

neutrophilic inflammation

(Han et al., 2014).

In these diseases,

modulating TLR activity

could help to restore immune homeostasis and

reduce chronic inflammation. Therapies that target

TLR4

signaling have been considered for

managing

COPD

, while

TLR9 agonists

could potentially be used in

chronic rhinosinusitis

to

enhance immune responses (Tsoyi et al., 2011).

TLR2 inhibitors

may provide therapeutic

benefits in treating

asthma

, where

TLR2 overexpression

exacerbates airway inflammation.

4. Personalized Medicine and TLR Polymorphisms

Another promising therapeutic approach involves

personalized medicine

based on an

individual's genetic makeup, specifically

TLR polymorphisms

. Variations in

TLR genes

can

affect the response to infection and influence the severity of diseases. For instance, individuals

with

TLR4 polymorphisms

may have altered responses to

Gram-negative bacterial infections

such as

pneumonia

and

sepsis

(Hoshino et al., 2002). Similarly,

TLR3 polymorphisms

may

affect susceptibility to viral infections like

influenza

and influence the

outcome

of the infection

(Takeuchi & Akira, 2007).

In

COVID-19

, certain

genetic variants

of

TLR7

have been associated with

severe disease

(van

der Made et al., 2020).

Personalized therapies

that consider these genetic differences could be

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tailored to optimize treatment and minimize adverse outcomes, leading to more effective and

targeted interventions.

5. Risks and Challenges in TLR-Based Therapies

Despite their potential, TLR-based therapies face several challenges.

Systemic TLR activation

can lead to unintended

side effects

, including

autoimmunity

,

chronic inflammation

, and tissue

damage. The challenge lies in developing

safe TLR agonists

and

antagonists

that can

specifically target the pathogen without inducing broad, unregulated immune activation.

Furthermore,

immune tolerance

or

immune evasion

by pathogens, especially

viruses

, could

limit the effectiveness of TLR-targeted therapies. Some viruses, such as

influenza

, have evolved

mechanisms to

evade TLR recognition

or dampen TLR signaling, making it more difficult to

achieve a strong immune response (Barton et al., 2007).

7. Conclusion

TLRs play a central role in the immune response to upper respiratory tract infections,

contributing to both effective pathogen clearance and inflammatory damage. Harnessing the

power of TLRs through

agonists

can enhance vaccine responses and boost immunity, while

antagonists

may provide a therapeutic strategy for preventing excessive inflammation in viral

and bacterial infections. Furthermore,

personalized approaches

, including targeting specific

TLR polymorphisms

, may lead to more tailored and effective treatments. However, careful

modulation of TLR activity is necessary to balance immune activation with the risk of unwanted

inflammation and tissue damage

References

1.

Bals, R., & Hiemstra, P. S. (2004). Innate immunity in the lung: How epithelial cells fight

against respiratory pathogens.

European Respiratory Journal

, 23(2), 327–333.

https://doi.org/10.1183/09031936.03.00098803

2.

Cohen, T. S., Prince, A. S. (2000). Bacterial pathogens and epithelial cell signaling:

Who's in control?

Cellular Microbiology

, 2(5), 305–314. https://doi.org/10.1046/j.1462-

5822.2000.00059.x

3.

Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S., & Reis e Sousa, C. (2004). Innate

antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.

Science

, 303(5663), 1529–1531. https://doi.org/10.1126/science.1093616

4.

Hajjar, A. M., Ernst, R. K., Tsai, J. H., Wilson, C. B., & Miller, S. I. (2002). Human Toll-

like receptor 4 recognizes host-specific LPS modifications.

Nature Immunology

, 3(4),

354–359. https://doi.org/10.1038/ni768

5.

Kaisho, T., & Akira, S. (2006). TLR signaling.

Seminars in Immunology

, 18(1), 24–32.

https://doi.org/10.1016/j.smim.2005.11.003

6.

Kawai, T., & Akira, S. (2010). The role of pattern-recognition receptors in innate

immunity: Update on Toll-like receptors.

Nature Immunology

, 11(5), 373–384.

https://doi.org/10.1038/ni.1863

7.

Kobayashi, K., Hernandez, L. D., Galán, J. E., Janeway, C. A., Medzhitov, R., & Flavell,

R. A. (2002). IRAK-M is a negative regulator of Toll-like receptor signaling.

Cell

, 110(2),

191–202. https://doi.org/10.1016/S0092-8674(02)00827-9

8.

Kurt-Jones, E. A., Popova, L., Kwinn, L., Haynes, L. M., Jones, L. P., Tripp, R. A., ... &

Finberg, R. W. (2000). Pattern recognition receptors TLR4 and CD14 mediate response

to

respiratory

syncytial

virus.

Nature

Immunology

,

1(5),

398–401.

https://doi.org/10.1038/80833

9.

Lane, A. P., Truong-Tran, Q. A., Myers, A., Bickel, C., & Schleimer, R. P. (2006).

Serum amyloid A, Toll-like receptors, and nasal epithelial innate immunity in chronic

rhinosinusitis.

American

Journal

of

Rhinology

,

20(3),

261–265.

https://doi.org/10.1177/194589240602000308

10.

Matsuo, K., Villena, J., Suzuki, T., & Aso, H. (2010). Immunogenicity and protective

efficacy of a nasal TLR2 ligand-based vaccine against influenza virus.

Vaccine

, 28(30),

5015–5022. https://doi.org/10.1016/j.vaccine.2010.05.010

https://ijmri.de/index.php/jmsi

volume 4, issue 4, 2025

479

11.

Takeuchi, O., Hoshino, K., Kawai, T., Sanjo, H., Takada, H., Ogawa, T., ... & Akira, S.

(1999). Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-

positive

bacterial

cell

wall

components.

Immunity

,

11(4),

443–451.

https://doi.org/10.1016/S1074-7613(00)80119-3

12.

van der Made, C. I., Simons, A., Schuurs-Hoeijmakers, J., et al. (2020). Presence of

genetic variants among young men with severe COVID-19.

JAMA

, 324(7), 663–673.

https://doi.org/10.1001/jama.2020.13719

13.

Albiger, B., Dahlberg, S., Sandgren, A., Wartha, F., Beiter, K., Katsuragi, H., ... &

Normark, S. (2005). Toll-like receptor 9 acts at an early stage in host defence against

pneumococcal

infection.

Cellular

Microbiology

,

7(7),

983–994.

https://doi.org/10.1111/j.1462-5822.2005.00519.x

14.

Beutler, B. (2000). TLR4: Central component of the sole mammalian LPS sensor.

Current Opinion in Immunology

, 12(1), 20–26. https://doi.org/10.1016/S0952-

7915(99)00049-4

15.

de Vos, A. F., Pater, J. M., van den Pangaart, P. S., de Kruif, M. D., van’t Veer, C., van

der Poll, T. (2009). Inhibition of TLR signaling in whole blood by IRAK4 and IKKβ

inhibitors: Effects on cytokine release and leukocyte activation.

Journal of Leukocyte

Biology

, 86(6), 1359–1368. https://doi.org/10.1189/jlb.0509320

16.

Hayashi, F., Smith, K. D., Ozinsky, A., Hawn, T. R., Yi, E. C., Goodlett, D. R., ... &

Aderem, A. (2001). The innate immune response to bacterial flagellin is mediated by

Toll-like receptor 5.

Nature

, 410(6832), 1099–1103. https://doi.org/10.1038/35074106

17.

Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., Sato, S., Sanjo, H., ... & Akira, S.

(2000). A Toll-like receptor recognizes bacterial DNA.

Nature

, 408(6813), 740–745.

https://doi.org/10.1038/35047123

18.

Hoshino, K., Takeuchi, O., Kawai, T., Sanjo, H., Ogawa, T., Takeda, Y., ... & Akira, S.

(2002). Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to

lipopolysaccharide: Evidence for TLR4 as the Lps gene product.

The Journal of

Immunology

, 162(7), 3749–3752.

19.

Leichtle, A., Hernandez, M., Pak, K., Yamasaki, K., Cheng, C. F., Webster, N. J. G., &

Ryan, A. F. (2009). TLR4-mediated induction of TLR2 expression in otitis media.

Infection and Immunity

, 77(12), 6273–6280. https://doi.org/10.1128/IAI.00725-09

20.

Melhus, A., & Ryan, A. F. (2000). Expression of Toll-like receptors in the mouse inner

ear and in response to acute otitis media.

The Annals of Otology, Rhinology, and

Laryngology

, 109(12), 1049–1056. https://doi.org/10.1177/000348940010901202

21.

Takeuchi, O., Kawai, T., Mühlradt, P. F., Morr, M., Radolf, J. D., Zychlinsky, A., ... &

Akira, S. (2001). Discrimination of bacterial lipoproteins by Toll-like receptor 6.

International Immunology

, 13(7), 933–940. https://doi.org/10.1093/intimm/dxf069

22.

Weiser, J. N., Ferreira, D. M., & Paton, J. C. (2018). Streptococcus pneumoniae:

Transmission, colonization and invasion.

Nature Reviews Microbiology

, 16(6), 355–367.

https://doi.org/10.1038/s41579-018-0001-8

23.

Zhang, X., Majlessi, L., Deriaud, E., Leclerc, C., & Lo-Man, R. (2007). Coactivation of

Syk kinase and MyD88 adaptor protein pathways by bacteria promotes regulatory

properties

of

neutrophils.

Immunity

,

26(5),

715–725.

https://doi.org/10.1016/j.immuni.2007.03.017