Dynamics of the blood plasma proteome during hyperacute HIV-1 infectionNazziwa, Freyhult, Hong
et alNat Commun (2024) 15 (1), 10593
Abstract: The complex dynamics of protein expression in plasma during hyperacute HIV-1 infection and its relation to acute retroviral syndrome, viral control, and disease progression are largely unknown. Here, we quantify 1293 blood plasma proteins from 157 longitudinally linked plasma samples collected before, during, and after hyperacute HIV-1 infection of 54 participants from four sub-Saharan African countries. Six distinct longitudinal expression profiles are identified, of which four demonstrate a consistent decrease in protein levels following HIV-1 infection. Proteins involved in inflammatory responses, immune regulation, and cell motility are significantly altered during the transition from pre-infection to one month post-infection. Specifically, decreased ZYX and SCGB1A1 levels, and increased LILRA3 levels are associated with increased risk of acute retroviral syndrome; increased NAPA and RAN levels, and decreased ITIH4 levels with viral control; and increased HPN, PRKCB, and ITGB3 levels with increased risk of disease progression. Overall, this study provides insight into early host responses in hyperacute HIV-1 infection, and present potential biomarkers and mechanisms linked to HIV-1 disease progression and viral load.© 2024. The Author(s).
Fibrinogen induces inflammatory responses via the immune activating receptor LILRA2Li, Hirayasu, Hasegawa
et alFront Immunol (2024) 15, 1435236
Abstract: The leukocyte immunoglobulin-like receptor (LILR) family, a group of primate-specific immunoreceptors, is widely expressed on most immune cells and regulates immune responses through interactions with various ligands. The inhibitory type, LILRB, has been extensively studied, and many ligands, such as HLA class I, have been identified. However, the activating type, LILRA, is less understood. We have previously identified microbially cleaved immunoglobulin as a non-self-ligand for LILRA2. In this study, we identified fibrinogen as an endogenous ligand for LILRA2 using mass spectrometry. Although human plasma contains fibrinogen in abundance in its soluble form, LILRA2 only recognizes solid-phase fibrinogen. In addition to the activating LILRA2, fibrinogen was also recognized by the inhibitory LILRB2 and by soluble LILRA3. In contrast, fibrin was recognized by LILRB2 and LILRA3, but not by LILRA2. Moreover, LILRA3 bound more strongly to fibrin than to fibrinogen and blocked the LILRB2-fibrinogen/fibrin interaction. These results suggest that morphological changes in fibrinogen determine whether activating or inhibitory immune responses are induced. Upon recognizing solid-phase fibrinogen, LILRA2 activated human primary monocytes and promoted the expression of various inflammation-related genes, such as chemokines, as revealed by RNA-seq analysis. A blocking antibody against LILRA2 inhibited the fibrinogen-induced inflammatory responses, indicating that LILRA2 is the primary receptor of fibrinogen. Taken together, our findings suggest that solid-phase fibrinogen is an inflammation-inducing endogenous ligand for LILRA2, and this interaction may represent a novel therapeutic target for inflammatory diseases.Copyright © 2024 Li, Hirayasu, Hasegawa, Tomita, Hashikawa, Hiwa, Arase and Hanayama.
Genome-Wide Association Analysis Identifies LILRB2 Gene for Pathological MyopiaJiang, Huang, Dai
et alAdv Sci (Weinh) (2024) 11 (40), e2308968
Abstract: Pathological myopia (PM) is one of the leading causes of blindness, especially in Asia. To identify the genetic risk factors of PM, a two-stage genome-wide association study (GWAS) and replication analysis in East Asian populations is conducted. The analysis identified LILRB2 in 19q13.42 as a new candidate locus for PM. The increased protein expression of LILRB2/Pirb (mouse orthologous protein) in PM patients and myopia mouse models is validated. It is further revealed that the increase in LILRB2/Pirb promoted fatty acid synthesis and lipid accumulation, leading to the destruction of choroidal function and the development of PM. This study revealed the association between LILRB2 and PM, uncovering the molecular mechanism of lipid metabolism disorders leading to the pathogenesis of PM due to LILRB2 upregulation.© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.
In Situ Analyses of Placental Inflammatory Response to SARS-CoV-2 Infection in Cases of Mother-Fetus Vertical TransmissionMorotti, Tabano, Gaudioso
et alInt J Mol Sci (2024) 25 (16)
Abstract: It has been shown that vertical transmission of the SARS-CoV-2 strain is relatively rare, and there is still limited information on the specific impact of maternal SARS-CoV-2 infection on vertical transmission. The current study focuses on a transcriptomics analysis aimed at examining differences in gene expression between placentas from mother-newborn pairs affected by COVID-19 and those from unaffected controls. Additionally, it investigates the in situ expression of molecules involved in placental inflammation. The Papa Giovanni XXIII Hospital in Bergamo, Italy, has recorded three instances of intrauterine transmission of SARS-CoV-2. The first two cases occurred early in the pandemic and involved pregnant women in their third trimester who were diagnosed with SARS-CoV-2. The third case involved an asymptomatic woman in her second trimester with a twin pregnancy, who unfortunately delivered two stillborn fetuses due to the premature rupture of membranes. Transcriptomic analysis revealed significant differences in gene expression between the placentae of COVID-19-affected mother/newborn pairs and two matched controls. The infected and control placentae were matched for gestational age. According to the Benjamani-Hochberg method, 305 genes met the criterion of an adjusted p-value of less than 0.05, and 219 genes met the criterion of less than 0.01. Up-regulated genes involved in cell signaling (e.g., CCL20, C3, MARCO) and immune response (e.g., LILRA3, CXCL10, CD48, CD86, IL1RN, IL-18R1) suggest their potential role in the inflammatory response to SARS-CoV-2. RNAscope® technology, coupled with image analysis, was utilized to quantify the surface area covered by SARS-CoV-2, ACE2, IL-1β, IL-6, IL-8, IL-10, and TNF-α on both the maternal and fetal sides of the placenta. A non-statistically significant gradient for SARS-CoV-2 was observed, with a higher surface coverage on the fetal side (2.42 ± 3.71%) compared to the maternal side (0.74 ± 1.19%) of the placenta. Although not statistically significant, the surface area covered by ACE2 mRNA was higher on the maternal side (0.02 ± 0.04%) compared to the fetal side (0.01 ± 0.01%) of the placenta. IL-6 and IL-8 were more prevalent on the fetal side (0.03 ± 0.04% and 0.06 ± 0.08%, respectively) compared to the maternal side (0.02 ± 0.01% and 0.02 ± 0.02%, respectively). The mean surface areas of IL-1β and IL-10 were found to be equal on both the fetal (0.04 ± 0.04% and 0.01 ± 0.01%, respectively) and maternal sides of the placenta (0.04 ± 0.05% and 0.01 ± 0.01%, respectively). The mean surface area of TNF-α was found to be equal on both the fetal and maternal sides of the placenta (0.02 ± 0.02% and 0.02 ± 0.02%, respectively). On the maternal side, ACE-2 and all examined interleukins, but not TNF-α, exhibited an inverse mRNA amount compared to SARS-CoV-2. On the fetal side, ACE-2, IL-6 and IL-8 were inversely correlated with SARS-CoV-2 (r = -0.3, r = -0.1 and r = -0.4, respectively), while IL-1β and IL-10 showed positive correlations (r = 0.9, p = 0.005 and r = 0.5, respectively). TNF-α exhibited a positive correlation with SARS-CoV-2 on both maternal (r = 0.4) and fetal sides (r = 0.9) of the placenta. Further research is needed to evaluate the correlation between cell signaling and immune response genes in the placenta and the vertical transmission of SARS-CoV-2. Nonetheless, the current study extends our comprehension of the molecular and immunological factors involved in SARS-CoV-2 placental infection underlying maternal-fetal transmission.
膜杰作
Star Staining
