| 1. |
- Demichev, Vadim, et al.
(författare)
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A time-resolved proteomic and prognostic map of COVID-19
- 2021
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Ingår i: Cell Systems. - : Elsevier BV. - 2405-4712 .- 2405-4720. ; 12:8, s. 780-794.e7
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Tidskriftsartikel (refereegranskat)abstract
- COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease.
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| 3. |
- Edfeldt, Gabriella, et al.
(författare)
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Regular Use of Depot Medroxyprogesterone Acetate Causes Thinning of the Superficial Lining and Apical Distribution of Human Immunodeficiency Virus Target Cells in the Human Ectocervix
- 2022
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 225:7, s. 1151-1161
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe hormonal contraceptive depot medroxyprogesterone acetate (DMPA) may be associated with an increased risk of acquiring human immunodeficiency virus (HIV). We hypothesize that DMPA use influences the ectocervical tissue architecture and HIV target cell localization.MethodsQuantitative image analysis workflows were developed to assess ectocervical tissue samples collected from DMPA users and control subjects not using hormonal contraception.ResultsCompared to controls, the DMPA group exhibited a significantly thinner apical ectocervical epithelial layer and a higher proportion of CD4+CCR5+ cells with a more superficial location. This localization corresponded to an area with a nonintact E-cadherin net structure. CD4+Langerin+ cells were also more superficially located in the DMPA group, although fewer in number compared to the controls. Natural plasma progesterone levels did not correlate with any of these parameters, whereas estradiol levels were positively correlated with E-cadherin expression and a more basal location for HIV target cells of the control group.ConclusionsDMPA users have a less robust epithelial layer and a more apical distribution of HIV target cells in the human ectocervix, which could confer a higher risk of HIV infection. Our results highlight the importance of assessing intact genital tissue samples to gain insights into HIV susceptibility factors.
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| 5. |
- Franzen-Röhl, Elisabeth, et al.
(författare)
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Increased cell-mediated immune responses in patients with recurrent herpes simplex virus type 2 meningitis.
- 2011
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Ingår i: Clinical and vaccine immunology : CVI. - 1556-679X. ; 18:4, s. 655-60
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Tidskriftsartikel (refereegranskat)abstract
- The clinical picture of herpes simplex virus type 2 (HSV-2) infection includes genital blisters and less frequently meningitis, and some individuals suffer from recurrent episodes of these manifestations. We hypothesized that adaptive and/or innate immune functional deficiencies may be a major contributing factor in susceptibility to recurrent HSV-2 meningitis. Ten patients with recurrent HSV-2 meningitis were studied during clinical remission. For comparison, 10 patients with recurrent genital HSV infections as well as 21 HSV-seropositive and 19 HSV-seronegative healthy blood donors were included. HSV-specific T cell blasting and cytokine secretion were evaluated in whole blood cultures. HSV-2-induced NK cell gamma interferon production, dendritic cell Toll-like receptor (TLR) expression, and TLR agonist-induced alpha interferon secretion were analyzed. Patients with recurrent HSV-2 meningitis had elevated T cell blasting and Th1 and Th2 cytokine production in response to HSV antigens compared to those of patients with recurrent genital infections. A somewhat increased NK cell response, increased dendritic cell expression of TLR3 and -9, and increased TLR-induced alpha interferon responses were also noted. Contrary to our expectation, recurrent HSV-2 meningitis patients have increased HSV-specific adaptive and innate immune responses, raising the possibility of immune-mediated pathology in the development of recurrent HSV2 meningitis.
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| 6. |
- Röhl, Maria
(författare)
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HIV susceptibility factors in the human genital mucosa
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Heterosexual HIV transmission is the most common viral transmission route worldwide. To establish a persistent infection the virus needs to cross the mucosal surface of the genital tract. The genital mucosa is thus considered to be the portal of HIV entry and initial site of viral replication. A better understanding of the immunological milieu at the portal of viral entry is crucial for the development of preventive interventions. In Paper I we investigated how herpes simplex virus 2 (HSV-2) affects the genital epithelial barrier and mucosal immune response in an HSV-2 seropositive, asymptomatic vs. HSV-2 seronegative male population in Kenya. The two study groups had comparable levels of all selected markers of inflammation and epithelial integrity, except for lower mRNA levels of the epithelial junction protein claudin-1 in the HSV-2 seropositive group, which may indicate a less robust genital epithelial barrier. In Paper II, we investigated how the use of progesterone-based hormonal contraceptives affects the genital epithelial barrier and mucosal HIV receptor expression in healthy Swedish women. The progesterone-based intrauterine device (pIUD) group was compared to a non-hormonal contraceptive (noHC) group and a combined oral hormonal contraceptives (COC) group. Similar protein expression levels of HIV receptors and co-receptors were observed in the three study groups. However, women using pIUD displayed a thinner apical layer of the ectocervical epithelium and lower mRNA levels of the epithelial junction protein ZO-1 as compared to the control groups. These results suggest that pIUD use may weaken the ectocervical epithelial barrier against invading pathogens, such as HIV. In Paper III, we further investigated how the use of hormonal contraceptives affects the production of antimicrobial peptides (AMPs) in different compartments of the female genital mucosa, including secretions and tissue. Women using COC had significantly lower mRNA levels of the AMPs BD-2 and trappin-2 in ectocervical tissue as compared to pIUD users. The two groups showed no differences in AMP protein expression in neither cervicovaginal secretion (CVS) nor in ectocervical tissue. These results suggest that the impact of sex hormones on local immune defences varies in tissue vs. secretions in the female genital tract. In Paper IV we examined if epithelial thickness and /or the quantity and localization of HIV target cells in ectocervical epithelium is associated to the relative resistance of HIV exposed seronegative (HESN) women. Thus, female sex workers defined as HESN were compared to control women who were relatively new to sex-work. Our results show that the HESN phenotype is not associated with an altered epithelial thickness or with altered levels or distributions of HIV target cells in the ectocervical epithelium. In summary, the studies characterized epithelial integrity in both the male and female genital tract, as well as the localization, distribution and quantity of immune cells and proteins in both tissue and secretions. These factors may be of importance for HIV susceptibility and was compared between study groups, characterized by various risk factors for HIV infection including HSV-2 infection, different types of hormonal contraceptive use and a phenotype of relative HIV resistance. Our results imply that the genital mucosa is a complex site and it is therefore of major importance to study the local immunological milieu in the tissues and not solely in secretions, which opens up for a much more comprehensive picture. Further, our data indicates that strengthening the genital epithelial barrier of the local genital mucosa may be a beneficial way to reduce sexual transmission of HIV, and should thus be incorporated in potential future prevention strategies against HIV infection.
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| 7. |
- Röhl, Samuel, et al.
(författare)
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Transcriptomic profiling of experimental arterial injury reveals new mechanisms and temporal dynamics in vascular healing response
- 2020
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Ingår i: JVS-Vascular Science. - : Elsevier BV. - 2666-3503. ; 315, s. E14-E14
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Endovascular interventions cause arterial injury and induce a healing response to restore vessel wall homeostasis. Complications of defective or excessive healing are common and result in increased morbidity and repeated interventions. Experimental models of intimal hyperplasia are vital for understanding the vascular healing mechanisms and resolving the clinical problems of restenosis, vein graft stenosis, and dialysis access failure. Our aim was to systematically investigate the transcriptional, histologic, and systemic reaction to vascular injury during a prolonged time. Methods: Balloon injury of the left common carotid artery was performed in male rats. Animals (n = 69) were euthanized before or after injury, either directly or after 2 hours, 20 hours, 2 days, 5 days, 2 weeks, 6 weeks, and 12 weeks. Both injured and contralateral arteries were subjected to microarray profiling, followed by bioinformatic exploration, histologic characterization of the biopsy specimens, and plasma lipid analyses. Results: Immune activation and coagulation were key mechanisms in the early response, followed by cytokine release, tissue remodeling, and smooth muscle cell modulation several days after injury, with reacquisition of contractile features in later phases. Novel pathways related to clonal expansion, inflammatory transformation, and chondro-osteogenic differentiation were identified and immunolocalized to neointimal smooth muscle cells. Analysis of uninjured arteries revealed a systemic component of the reaction after local injury, underlined by altered endothelial signaling, changes in overall tissue bioenergy metabolism, and plasma high-density lipoprotein levels. Conclusions: We demonstrate that vascular injury induces dynamic transcriptional landscape and metabolic changes identifiable as early, intermediate, and late response phases, reaching homeostasis after several weeks. This study provides a temporal “roadmap” of vascular healing as a publicly available resource for the research community.
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