The Impact of Aging and Toll-like Receptor 2 Deficiency on the Clinical Outcomes of <i>Staphylococcus aureus</i> Bacteremia

Hu, Zhicheng; Kopparapu, Pradeep Kumar; Deshmukh, Meghshree; Jarneborn, Anders; Gupta, Priti; Ali, Abukar; Fu, Ying; Engdahl, Cecilia; Pullerits, Rille; Mohammad, Majd; Jin, Tao

doi:10.1093/infdis/jiad046

Cited by 5 publications

(5 citation statements)

References 35 publications

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“…According to a prior study, TLR2 plays an important role in the synthesis of immunoglobulins by shaping their response to the disease 27 . Indeed, the clinical data from the same experimental setting have demonstrated that age and TLR2 deficiency synergically aggravated the S. aureus bacteremia 14 . The mortality and spleen weight changes caused by S. aureus bacteremia and are controlled by aging, whereas other clinical parameters such as weight loss and kidney abscesses are TLR2 dependent.…”

Section: Discussionmentioning

confidence: 97%

“…The change in the humoral response during aging contributes significantly to the elderly's susceptibility to infectious disease and reduces the protective effects of treatment or vaccination. In using the same experimental setting, Hu et al; 2023, demonstrated that both aging and TLR2 deficiency enhanced bacteremia 14 . Aging and TLR deficiency enhanced disease susceptibility, but only aging increased mortality.…”

Section: Introductionmentioning

confidence: 99%

“…SpA has a complex structure with several immunoglobulin binding sites 13 . S. aureus bacteremia displays higher mortalities than bacteremia caused by most other microbes 8 , 14 . Toll-like receptor 2 (TLR2) recognizes staphylococcal lipoproteins that are one of the pathogens associated molecular patterns on S. aureus and play a potent role in the pathogenesis of staphylococcal infections 15 .…”

Section: Introductionmentioning

confidence: 99%

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The impact of TLR2 and aging on the humoral immune response to Staphylococcus aureus bacteremia in mice

Gupta

Kopparapu

et al. 2023

Sci Rep

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Aging alters immunoglobulin production, affecting the humoral immune response. Toll-like receptor 2 (TLR2) recognizes Staphylococcus aureus (S. aureus) which causes bacteremia with high mortality in the elderly. To understand how TLR2 and aging affect the humoral immune response in bacteremia, four groups of mice (wild type-young, wild type-old, TLR2−/−-young, and TLR2−/−-old) were used to analyze immunoglobulin levels in healthy conditions as well as 10 days after intravenous injection with S. aureus. We found that aging increased the levels of both IgM and IgG. Increased IgG in aged mice was controlled by TLR2. In bacteremia infection, aged mice failed to mount proper IgM response in both wild-type (WT) and TLR2−/− mice, whereas IgG response was impaired in both aged and TLR2−/− mice. Aged mice displayed reduced IgG1 and IgG2a response irrespective of TLR2 expression. However, impaired IgG2b response was only found in aged WT mice and not in TLR2−/− mice. Both aging and TLR2−/− increased the levels of anti-staphylococcal IgM in bacteremia. Aging increased sialylated IgG in WT mice but not in TLR2−/− mice. IgG sialylation was not affected by the infection in neither of the mice. In summary, aging increases all immunoglobulins except IgG1. However, aged mice fail to mount a proper antibody response to S. aureus bacteremia. TLR2 plays the regulatory role in IgG but not IgM response to infection.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The impact of TLR2 and aging on the humoral immune response to Staphylococcus aureus bacteremia in mice

Gupta

Kopparapu

et al. 2023

Sci Rep

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“…Mice were kept under standard temperature and light conditions and were fed laboratory chow and water ad libitum . As prior studies did not reveal a noteworthy impact of sex difference on the outcomes of S. aureus hematogenous septic arthritis in mouse models ( Hu et al, 2023 ), we opted to exclusively employ female mice in current study. The Ethics Committee of Animal Research of Gothenburg approved the study, and the animal experimentation guidelines of the Swedish Board of Agriculture were strictly followed.…”

Section: Methodsmentioning

confidence: 99%

Gene expression of S100a8/a9 predicts Staphylococcus aureus-induced septic arthritis in mice

Deshmukh

Subhash

et al. 2023

Front. Microbiol.

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Septic arthritis is the most aggressive joint disease associated with high morbidity and mortality. The interplay of the host immune system with the invading pathogens impacts the pathophysiology of septic arthritis. Early antibiotic treatment is crucial for a better prognosis to save the patients from severe bone damage and later joint dysfunction. To date, there are no specific predictive biomarkers for septic arthritis. Transcriptome sequencing analysis identified S100a8/a9 genes to be highly expressed in septic arthritis compared to non-septic arthritis at the early course of infection in an Staphylococcus aureus septic arthritis mouse model. Importantly, downregulation of S100a8/a9 mRNA expression at the early course of infection was noticed in mice infected with the S. aureus Sortase A/B mutant strain totally lacking arthritogenic capacity compared with the mice infected with parental S. aureus arthritogenic strain. The mice infected intra-articularly with the S. aureus arthritogenic strain significantly increased S100a8/a9 protein expression levels in joints over time. Intriguingly, the synthetic bacterial lipopeptide Pam2CSK4 was more potent than Pam3CSK4 in inducing S100a8/a9 release upon intra-articular injection of these lipopeptides into the mouse knee joints. Such an effect was dependent on the presence of monocytes/macrophages. In conclusion, S100a8/a9 gene expression may serve as a potential biomarker to predict septic arthritis, enabling the development of more effective treatment strategies.

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“…Advanced age has been recognized as a significant risk factor for septic arthritis in patients ( Kaandorp et al, 1995 ). Nonetheless, our recent study, employing aging and TLR-2 deficient mice, disclosed that increased age stood out as the primary contributor to heightened mortality rates and changes in spleen weight ( Hu et al, 2023 ). Surprisingly, the severity of septic arthritis remained unaltered by aging, even though aged mice demonstrated an insufficient antibody response to S. aureus infection ( Gupta et al, 2023 ).…”

Section: To Study the Role Of Host Factors In Septic Arthritismentioning

confidence: 99%

Exploring the role of bacterial virulence factors and host elements in septic arthritis: insights from animal models for innovative therapies

Jin

2024

Front. Microbiol.

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Septic arthritis, characterized as one of the most aggressive joint diseases, is primarily attributed to Staphylococcus aureus (S. aureus) and often results from hematogenous dissemination. Even with prompt treatment, septic arthritis frequently inflicts irreversible joint damage, leading to sustained joint dysfunction in a significant proportion of patients. Despite the unsatisfactory outcomes, current therapeutic approaches for septic arthritis have remained stagnant for decades. In the clinical context, devising innovative strategies to mitigate joint damage necessitates a profound comprehension of the pivotal disease mechanisms. This entails unraveling how bacterial virulence factors interact with host elements to facilitate bacterial invasion into the joint and identifying the principal drivers of joint damage. Leveraging animal models of septic arthritis emerges as a potent tool to achieve these objectives. This review provides a comprehensive overview of the historical evolution and recent advancements in septic arthritis models. Additionally, we address practical considerations regarding experimental protocols. Furthermore, we delve into the utility of these animal models, such as their contribution to the discovery of novel bacterial virulence factors and host elements that play pivotal roles in the initiation and progression of septic arthritis. Finally, we summarize the latest developments in novel therapeutic strategies against septic arthritis, leveraging insights gained from these unique animal models.

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The Impact of Aging and Toll-like Receptor 2 Deficiency on the Clinical Outcomes of Staphylococcus aureus Bacteremia

Cited by 5 publications

References 35 publications

The impact of TLR2 and aging on the humoral immune response to Staphylococcus aureus bacteremia in mice

The impact of TLR2 and aging on the humoral immune response to Staphylococcus aureus bacteremia in mice

Gene expression of S100a8/a9 predicts Staphylococcus aureus-induced septic arthritis in mice

Exploring the role of bacterial virulence factors and host elements in septic arthritis: insights from animal models for innovative therapies

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