Damage-associated molecular patterns and pathogen-associated molecular patterns in severe bacterial infections

Abstract

<p dir="ltr">Community-acquired bacterial infections can range from mild to severe, including sepsis. The mechanisms driving severe disease and poor outcomes remain unclear. The early host response in sepsis is triggered by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), which activate the innate immune system. However, the relationship between DAMP and PAMP levels, their dynamics during the disease, and their role in the development of severe illness, is not fully understood. This thesis aimed to explore DAMPs and PAMPs in severe bacterial infections, focusing on their interrelationship and how their systemic and local concentrations correlate with disease severity.</p><p dir="ltr">Study I assessed the relationship between clinical and microbiological factors and the nasopharyngeal (NP) density of Streptococcus pneumoniae in 57 adults hospitalised with pneumococcal community-acquired pneumonia (CAP) and whether high NP density could indicate severe disease. It was found that high NP pneumococcal density was linked to severe pneumonia, longer symptom duration (≥2 days), and a higher serum immunoglobulin titre against the patient’s pneumococcal serotype. However, NP density was not found to be useful for reliably detecting severe pneumococcal pneumonia.</p><p dir="ltr">In Study II, we investigated the relationship between high mobility group box 1 (HMGB1), a DAMP, and lytA DNA load, a PAMP, with disease severity and aetiology in CAP. Among 111 hospitalised patients, HMGB1 levels in plasma and sputum showed no correlation with disease severity. However, elevated sputum HMGB1 was associated with pneumococcal aetiology. In cases of pneumococcal CAP, a high sputum lytA DNA load was linked to respiratory failure, while elevated sputum HMGB1 was associated with bacteraemia. These findings indicate that although sputum HMGB1 is not associated with disease severity, it may play a role in bacterial dissemination, whereas a high lytA load is associated with severe disease.</p><p dir="ltr">Study III analysed whether plasma and sputum levels of soluble thrombomodulin were associated with disease severity in 111 patients with bacterial CAP and whether these levels varied across different bacterial aetiologies. Plasma thrombomodulin concentrations were elevated in patients with severe pneumococcal CAP, but not in those with severe CAP caused by other bacteria or in cases of non-severe pneumococcal CAP. This suggests that plasma thrombomodulin may serve as a potential biomarker for detecting severe pneumococcal pneumonia. Conversely, sputum thrombomodulin concentrations were not associated with disease severity or bacterial aetiology. </p><p dir="ltr">Study IV examined the role of four DAMPs, nuclear DNA (nDNA), mitochondrial DNA (mtDNA), heat shock protein 90 alpha (HSP90α), and HMGB1, and their dynamics in relation to disease severity and negative outcomes, compared to the previously analysed PAMP, 16S rDNA, in a cohort of 83 patients with bacteraemic infections caused by S. pneumoniae, Staphylococcus aureus, or Escherichia coli. Among the DAMPs, nDNA outperformed the others in sepsis detection and outcome prediction. In the comparison between DAMP and PAMP, a significant correlation was observed between them; nevertheless, both nDNA (a DAMP) and 16S rDNA (a PAMP) were independently associated with sepsis, with nDNA also being linked to negative outcomes and remaining persistently elevated in these cases.<br><br>List of scientific papers<br></p><p dir="ltr"><br></p><p dir="ltr">I. Clinical and microbiological factors associated with high nasopharyngeal pneumococcal density in patients with pneumococcal pneumonia. <b>Helena Alpkvist</b>, Simon Athlin, Pontus Nauclér, Björn Herrmann, Guma Abdeldaim, Hans-Christian Slotved, Jonas Hedlund, Kristoffer Strålin. <br>PLoS One, 2015 Oct 14;10(10):e0140112. <a href="https://doi.org/10.1371/journal.pone.0140112" target="_blank">https://doi.org/10.1371/journal.pone.0140112<br></a></p><p dir="ltr"><br></p><p dir="ltr">II. High HMGB1 levels in sputum are related to pneumococcal bacteraemia but not to disease severity in community-acquired pneumonia. <b>Helena Alpkvist</b>, Simon Athlin, Paula Mölling, Anna Norrby-Teglund, Kristoffer Strålin. <br>Scientific Reports, 2018 Sep 7;8(1):13428. <a href="https://doi.org/10.1038/s41598-018-31504-4" rel="noreferrer" target="_blank">https://doi.org/10.1038/s41598-018-31504-4<br><br></a></p><p dir="ltr">III. Plasma and sputum thrombomodulin in bacterial community-acquired pneumonia. <b>Helena Alpkvist</b>, Simon Athlin, Anna Norrby-Teglund, Kristoffer Strålin. [Submitted]</p><p dir="ltr">IV. Damage-associated molecular patterns in bacteraemic infection, including a comparative analysis with bacterial DNA, a pathogen-associated molecular pattern. <b>Helena Alpkvist</b>, Ingrid Ziegler, Paula Mölling, Elisabet Tina, Linnea Sellvén, Anna Norrby-Teglund, Sara Cajander<i>, </i>Kristoffer Strålin. <br>Scientific Reports, 2024 Oct 8;14(1):23499. <a href="https://doi.org/10.1038/s41598-024-74868-6" rel="noreferrer" target="_blank">https://doi.org/10.1038/s41598-024-74868-6</a> <br>* = equal contribution.</p><p dir="ltr"><br></p><p dir="ltr"><br></p>