The research, published in the journal Immunity, Inflammation and Disease, was conceived as a direct replication attempt of an earlier Iranian study that had reported a worrying association. That study, led by Kolsari and colleagues, found that carriers of the TT genotype at a specific variant in the SFTPD gene, known as rs721917, were more likely to be hospitalized and to suffer severe symptoms after SARS-CoV-2 infection. The TT genotype appeared more frequently among patients admitted to intensive care and cardiac care units than the CC genotype, and it was linked to higher overall hospitalization rates. If correct, the finding would have identified a common genetic variant, present in roughly a third of many populations, as a risk factor for severe disease.

To test this, a team at the Institute for Clinical and Experimental Medicine in Prague, led by Jaroslav A. Hubacek, analyzed the same polymorphism in a much larger Czech cohort. The variant rs721917 is a single-letter change in the DNA sequence, a C-to-T substitution that alters the amino acid at position 31 of the SP-D protein, replacing methionine with threonine. This region of the protein matters functionally, because SP-D is a collectin, a molecule that binds both pathogens and immune cells, helping to clear viruses and bacteria from the lungs while modulating inflammation. Genetic variation in this gene is therefore a biologically plausible candidate for influencing the course of a respiratory infection such as COVID-19.

The Czech researchers used a PCR-based restriction fragment length polymorphism assay to genotype 436 adults with confirmed SARS-CoV-2 infection, of whom 164 had remained completely asymptomatic and 272 had developed symptoms. They compared these patients with 467 adult population controls drawn from the Czech post-MONICA study, a long-running cardiovascular risk survey that provides a representative sample of the national population. Infection status was confirmed by PCR screening, and follow-up extended until December 2024, ensuring that participants’ infection histories were reliably documented. Statistical analyses were performed with SPSS Statistics 27.

The first reassuring observation was that genotype distributions in both patients and controls conformed to the Hardy-Weinberg equilibrium, the genetic baseline that indicates a population is mating randomly and that genotyping is technically sound. The equilibrium probabilities were p equals 0.80 for controls and p equals 0.24 for patients. When the researchers compared the entire group of SARS-CoV-2-positive individuals with the controls, they found no significant difference in genotype frequencies, with a p-value of 0.59. In other words, carrying any particular version of rs721917 did not appear to influence whether a person became infected in the first place.

The more interesting results emerged when the patients were stratified by disease course. Genotype frequencies differed significantly between asymptomatic subjects and population controls, with a p-value of 0.02, and between asymptomatic subjects and symptomatic patients, with a p-value of 0.01. The driving force behind these differences was a higher proportion of heterozygotes, individuals carrying one C and one T allele, among the asymptomatic group, where they made up 60.3 percent of subjects compared with 47.8 percent of controls and 45.6 percent of symptomatic patients. The researchers caution that such an excess of heterozygotes raises the possibility of an overdominant effect, in which having two different versions of the gene confers an advantage over having two identical copies.

A second pattern pointed in the same direction. The frequency of the CC genotype rose in a borderline, nonsignificant trend, with p equal to 0.08, from the asymptomatic group through the population controls to the symptomatic subjects. Consistent with this gradient, carriers of at least one T allele were slightly less likely to appear in the symptomatic COVID-19 group than CC homozygotes, with an odds ratio of 0.59 and a 95 percent confidence interval of 0.34 to 1.05, at a nominal p-value of 0.07. This is the opposite direction of association to that reported in the Iranian study, which had flagged the T-bearing TT genotype as a risk factor rather than a protective one.

The authors offer several explanations for the discrepancy. The original Iranian study was small, with only between 17 and 42 subjects in each severity category, spanning mild, moderate, severe, and critical courses of COVID-19. Samples of that size are notoriously prone to false positive results, particularly in genetic association studies where many variants are tested simultaneously. More troubling still, the genotype frequencies in the Iranian cohort deviated dramatically from the Hardy-Weinberg expectation, with a p-value below 0.0000001. Such a marked deviation complicates interpretation and may reflect ascertainment bias, hidden population structure, or genotyping inaccuracies, any of which could produce a spurious association. Interethnic differences in genetic susceptibility to SARS-CoV-2 infection are also well documented, providing a further possible reason why results from an Iranian population might not replicate in Central Europeans.

Crucially, the Czech findings align with the largest genetic evidence base available. A major meta-analysis of genome-wide association studies, published in Nature by Pairo-Castineira and colleagues, identified 49 genetic variants associated with critical COVID-19, and rs721917 was among them. In that analysis, the T allele was associated with approximately a 7 percent lower risk of critical disease, a result that supports the Czech case-control finding, where the T allele showed a nominal 4 percent decrease in risk of symptomatic illness. The convergence of an independent large-scale GWAS meta-analysis with a targeted replication study strengthens the conclusion that the T allele is not a risk factor, and may instead confer modest protection against severe or symptomatic COVID-19.

The picture is rounded out by studies of the protein itself. Two investigations measured circulating concentrations of SP-D and reached similar conclusions. No difference in plasma SP-D levels was observed between 141 convalescent COVID-19 patients examined ten weeks after infection and 98 uninfected subjects, and in a separate pediatric cohort of 325 children, SP-D levels were not associated with COVID-19 severity. In children, the SFTPD rs721917 polymorphism likewise showed no effect on disease severity. The authors also note, somewhat surprisingly, that despite the strong biological plausibility of SFTPD as a susceptibility gene, no further adult studies outside GWAS analyses have been published on this topic, underscoring how much remains to be learned. Taken together, the Czech results and the wider literature suggest that carriers of the T allele at rs721917 are potentially protected, rather than placed at increased risk, against symptomatic or severe forms of COVID-19, though the authors emphasize that further studies are needed to detect potential ethnic-specific effects of this variant across different populations.

Subject of Research: Association between the SFTPD rs721917 polymorphism and susceptibility to symptomatic and severe COVID-19 in the Czech population

Article Title: Surfactant‐Associated Protein D Polymorphism and Protection Against COVID‐19 in the Czech Population

Article References: Hubacek, J. A., Philipp, T., Ondrackova, M., Adamkova, V., & Dusek, L. (2026). Surfactant‐Associated Protein D Polymorphism and Protection Against COVID‐19 in the Czech Population. Immunity, Inflammation and Disease, 14(10), Article e70541. https://doi.org/10.1002/iid3.70541

Image Credits: AI Generated

DOI: 10.1002/iid3.70541

Keywords: SFTPD, surfactant protein D, rs721917, COVID-19, SARS-CoV-2, genetic polymorphism, host genetics, case-control study, Hardy-Weinberg equilibrium, GWAS meta-analysis, Czech population, innate immunity

The team, led by researchers at Sun Yat-sen University in Guangzhou, China, focused on tissue-resident alveolar macrophages, or TR-AMs, the long-lived sentinels that populate the alveoli, the tiny air sacs where oxygen exchange takes place. These cells originate from fetal liver monocytes and sustain themselves largely without replacement from the bloodstream, outnumbering interstitial macrophages in the lung by roughly eight to one. Under healthy conditions, they patrol nearly continuously between alveoli, engulfing inhaled bacteria, particles, and dying cells, while also clearing and catabolizing excess pulmonary surfactant, the lipid-protein film that keeps the air sacs from collapsing. Nearly ninety percent of them actively migrate as part of routine immune surveillance, making them both the lung’s first responders and its housekeeping crew.

Previous work on particulate pollution and macrophages had largely relied on monocyte-derived cell lines such as THP-1 and U937, which model recruited immune cells rather than the resident alveolar lineage. The new study set out to close that gap by examining how diesel particulate matter, or DPM, affects the two physiological functions that define TR-AM biology: chemotactic movement and phagocytosis. DPM is a major contributor to fine particulate pollution in urban and industrialized environments, and roughly half to ninety percent of it consists of ultrafine particles smaller than 0.1 micrometers, small enough to penetrate deep into the alveolar spaces where these macrophages live.

The researchers began with the murine alveolar macrophage cell line MH-S, exposing cells to a standardized DPM preparation for 24 hours and then performing RNA sequencing. The exposure produced sweeping transcriptional changes, with 287 genes upregulated and 219 downregulated. Pathway analysis revealed disruption in phagosome and actin cytoskeleton regulation, bacterial recognition, and cytokine signaling. Genes encoding integrins and complement receptors essential for adhesion, migration, and bacterial uptake, including Itgal, Itgam, Fpr1, Fpr2, C5ar1, C1qa, and C1qc, were significantly suppressed, and flow cytometry confirmed reduced surface expression of the CD11a and CD11b integrin proteins.

Functional testing followed. In transwell migration assays, DPM-treated macrophages showed a dramatic loss of their ability to migrate toward chemoattractants produced at sites of bacterial stimulation. Notably, the cells’ secretion of chemokines, the signals used to recruit other immune cells, was largely unchanged, suggesting that diesel particles primarily cripple the macrophages’ own motility and receptor signaling rather than their communication role. Phagocytosis assays using fluorescently labeled Escherichia coli and Staphylococcus aureus bioparticles showed sharply reduced uptake and impaired phagosome acidification in DPM-exposed cells, indicating that both particle engulfment and the maturation of the digestive compartment were compromised.

To confirm these findings in living animals, the team exposed mice to DPM via intratracheal instillation and then delivered fluorescent bacterial bioparticles directly into the airways. Primary TR-AMs, identified by their characteristic CD45-high SiglecF-positive surface profile, showed a marked reduction in the ability to phagocytose both bacterial species, and the proportion of highly phagocytic cells fell substantially. The deficit proved durable: phagocytic capacity remained suppressed for weeks after exposure, with only a gradual recovery trend over an eight-week observation period. Conditioned-medium experiments showed that the effect was driven mainly by direct contact between particles and macrophages, though epithelial cells exposed to DPM released soluble mediators that added a smaller, indirect layer of inhibition.

The mechanistic core of the study lies in the actin cytoskeleton. Both migration and phagocytosis depend on the polymerization of filamentous actin, or F-actin, which provides the mechanical force for cell deformation, filopodia extension, and the engulfment of particles larger than half a micrometer. DPM exposure significantly reduced phalloidin staining of F-actin in macrophages, and the loss of polymerization tracked closely with a more than tenfold decrease in bacterial uptake. When the researchers treated cells with cytochalasin D, a drug that disrupts filamentous actin, phagocytosis collapsed in the same way, confirming that actin remodeling is indispensable for the process. DPM also reduced the expression of the upstream regulators of actin nucleation, including the GTPases Rac1 and Cdc42, the nucleation-promoting factors WASP, N-WASP, and WAVE, and the Arp2 and Arp3 components of the actin-nucleating complex, pointing to suppression of the Rac1/Cdc42-WASP-Arp2/3 signaling cascade as a likely driver of the functional failure.

The downstream consequences for lung physiology were equally striking. Because TR-AMs are responsible for clearing excess surfactant, their paralysis led to measurable accumulation in the alveoli. Mice exposed to DPM developed Periodic acid-Schiff-positive granules in the alveolar spaces, a histological signature of accumulated surfactant glycoproteins and lipoprotein deposits. Bronchoalveolar lavage fluid showed sharply elevated total protein, a roughly 120-fold increase in surfactant protein D, elevated lactate dehydrogenase indicating cell death, and a slight decline in surfactant protein A, the collectin that normally facilitates lipid clearance. Targeted lipidomics revealed excessive accumulation of phosphatidylcholine species that normally constitute the bulk of surfactant lipids, along with ceramides and free cholesterol. In vitro, DPM-treated macrophages showed significantly reduced uptake of fluorescent cholesterol, linking the cellular defect directly to the lipid buildup observed in the animals.

That pattern, the authors note, closely resembles pulmonary alveolar proteinosis, a disease in which surfactant accumulates, gas exchange fails, and infection risk rises. While primary forms of the disease stem from defects in granulocyte-macrophage colony-stimulating factor signaling, secondary alveolar proteinosis arises from external insults that deplete or disable alveolar macrophages, and inhaled particles including indium and gallium compounds have already been implicated. The new findings suggest that diesel particulate exposure may represent another route to this pathology, offering a mechanistic bridge between everyday air pollution and a condition that is frequently underdiagnosed.

The researchers are careful to acknowledge the limits of their model. The acute murine exposure protocol compresses what would be months of real-world inhalation into concentrated instillations, and although the authors estimate that the cumulative dose corresponds to roughly six days of occupational exposure in a high-concentration underground mining environment, long-term inhalation studies will be needed to confirm relevance to ordinary urban exposure. The evidence linking the Rac1/Cdc42-WASP-Arp2/3 pathway to the observed dysfunction remains correlative, and direct measurement of chemotaxis in primary TR-AMs was not performed. Even so, the study delivers a clear and consequential message: the same soot that darkens city air can quietly disarm the lung’s resident defenders, weakening immune surveillance, delaying inflammation resolution, and allowing surfactant to accumulate where it can do real harm. Restoring macrophage actin dynamics, the authors suggest, may one day offer a therapeutic strategy for pollution-related respiratory disease.

Subject of Research: Impairment of tissue-resident alveolar macrophage phagocytosis by diesel particulate matter and its role in pulmonary surfactant accumulation

Article Title: Phagocytotic impairment of tissue-resident alveolar macrophages by diesel particulates drives pulmonary surfactant accumulation

Article References: Chen, R., Zhou, Z., Wang, J., Zhang, Y., Li, P., & Wu, H. (2026). Phagocytotic impairment of tissue-resident alveolar macrophages by diesel particulates drives pulmonary surfactant accumulation. Advanced Biotechnology, 4(2), Article 21. https://doi.org/10.1007/s44307-026-00113-y

Image Credits: AI Generated

DOI: 10.1007/s44307-026-00113-y

Keywords: diesel particulate matter, alveolar macrophages, phagocytosis, chemotaxis, F-actin, pulmonary surfactant, pulmonary alveolar proteinosis, air pollution, PM2.5, innate immunity, surfactant protein D, lipidomics