| 1. |
- Carlsson, Marcus, et al.
(författare)
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A note on variable susceptibility, the herd-immunity threshold and modeling of infectious diseases
- 2023
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- The unfolding of the COVID-19 pandemic has been very difficult to predict using mathematical models for infectious diseases. While it has been demonstrated that variations in susceptibility have a damping effect on key quantities such as the incidence peak, the herd-immunity threshold and the final size of the pandemic, this complex phenomenon is almost impossible to measure or quantify, and it remains unclear how to incorporate it for modeling and prediction. In this work we show that, from a modeling perspective, variability in susceptibility on an individual level is equivalent with a fraction θ of the population having an “artificial” sterilizing immunity. We also derive novel formulas for the herd-immunity threshold and the final size of the pandemic, and show that these values are substantially lower than predicted by the classical formulas, in the presence of variable susceptibility. In the particular case of SARS-CoV-2, there is by now undoubtedly variable susceptibility due to waning immunity from both vaccines and previous infections, and our findings may be used to greatly simplify models. If such variations were also present prior to the first wave, as indicated by a number of studies, these findings can help explain why the magnitude of the initial waves of SARS-CoV-2 was relatively low, compared to what one may have expected based on standard models.
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| 2. |
- Carlsson, Marcus, et al.
(författare)
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COVID-19 Modeling Outcome versus Reality in Sweden
- 2022
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Ingår i: Viruses. - : MDPI AG. - 1999-4915. ; 14:8
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Tidskriftsartikel (refereegranskat)abstract
- It has been very difficult to predict the development of the COVID-19 pandemic based on mathematical models for the spread of infectious diseases, and due to major non-pharmacological interventions (NPIs), it is still unclear to what extent the models would have fit reality in a “do nothing” scenario. To shed light on this question, the case of Sweden during the time frame from autumn 2020 to spring 2021 is particularly interesting, since the NPIs were relatively minor and only marginally updated. We found that state of the art models are significantly overestimating the spread, unless we assume that social interactions significantly decrease continuously throughout the time frame, in a way that does not correlate well with Google-mobility data nor updates to the NPIs or public holidays. This leads to the question of whether modern SEIR-type mathematical models are unsuitable for modeling the spread of SARS-CoV-2 in the human population, or whether some particular feature of SARS-CoV-2 dampened the spread. We show that, by assuming a certain level of pre-immunity to SARS-CoV-2, we obtain an almost perfect data-fit, and discuss what factors could cause pre-immunity in the mathematical models. In this scenario, a form of herd-immunity under the given restrictions was reached twice (first against the Wuhan-strain and then against the alpha-strain), and the ultimate decline in cases was due to depletion of susceptibles rather than the vaccination campaign.
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| 3. |
- Dzabic, Mensur, et al.
(författare)
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Intragraft Cytomegalovirus Protein Expression Is Associated With Reduced Renal Allograft Survival
- 2011
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Ingår i: Clinical Infectious Diseases. - : Oxford University Press (OUP). - 1058-4838 .- 1537-6591. ; 53:10, s. 969-976
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cytomegalovirus (CMV) infection is a risk factor for acute and chronic rejection of transplanted organs and is thought to mediate rejection indirectly. Methods: In this retrospective observational cohort study, early- and end-stage biopsies from renal allografts lost because of chronic allograft dysfunction (n = 29) were examined for CMV antigens and DNA using immunohistochemistry, in situ hybridization, and real-time polymerase chain reaction. Results: CMV immediate-early and late proteins were present in 27 (93%) of 29 of the end-stage chronic allograft dysfunction biopsies and in 64% of the corresponding early biopsies but not in pretransplant biopsies from CMV-seronegative donors (n = 3). Graft survival time was reduced in patients with moderate or high CMV levels in the graft soon after transplantation compared with that in patients with no or low CMV levels in the graft. No significant difference was observed in serum creatinine obtained at the time of early biopsies. Conclusions: We provide evidence that intragraft CMV protein expression is associated with end-stage chronic renal allograft dysfunction, that intragraft CMV levels increase as graft function deteriorates, and that CMV protein expression in the grafts soon after transplant is associated with reduced graft survival. Thus, CMV may have a pathological role in chronic renal allograft dysfunction.
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| 4. |
- Gredmark-Russ, Sara, et al.
(författare)
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Active cytomegalovirus infection in aortic smooth muscle cells from patients with abdominal aortic aneurysm
- 2009
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Ingår i: Journal of Molecular Medicine. - : Springer Science and Business Media LLC. - 0946-2716 .- 1432-1440. ; 87:4, s. 347-356
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Tidskriftsartikel (refereegranskat)abstract
- Cytomegalovirus (CMV) is associated with atherosclerosis and transplant vascular sclerosis. The aim of this study was to explore the hypothesis that active CMV infection in the vessel wall could be associated with abdominal aortic aneurysm (AAA). We examined the prevalence of CMV in AAA specimens from 22 patients undergoing surgery and, in five cases, characterized the function of smooth muscle cells (SMCs) from the aneurysm in vitro. Twenty-one (95%) of the 22 AAA specimens were CMV positive by a polymerase chain reaction assay, in situ hybridization, or a highly sensitive immunohistochemical staining technique. No positive cells were found in aortas from three CMV-seronegative organ donor cadavers. CMV immediate-early and late antigens were expressed in SMCs in the lesions and were associated with 5-lipoxygenase (5-LO) expression. CMV-positive intimal SMCs migrated 6.6 +/- 1.5 times more efficiently than CMV-negative medial SMCs (p < 0.05). In vitro CMV infection of medial SMCs resulted in a 3.2 +/- 1.2 times increase in migration (p < 0.05). The intimal migration was significantly inhibited by antibodies against basic fibroblast growth factor (bFGF; p < 0.05) in a dose-dependent fashion. Antibodies against platelet-derived growth factor (PDGF)-AB, insulin-like growth factor 1, vascular endothelial growth factor (VEGF), RANTES, monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein (MIP)-1alpha, or interleukin-1beta did not significantly affect intimal SMC migration. However, intimal and medial SMCs secreted similar amounts of bFGF, MCP-1, MIP-1alpha, RANTES, PDGF-AB, PDGF-BB, epidermal growth factor, and VEGF. CMV infection in vitro of intimal and medial cells did not result in significant changes of bFGF or MCP-1 secretion. Since CMV infection can affect several functional parameters in SMCs, including several key factors in infected SMCs, our findings provide support for the hypothesis that CMV contributes to the pathogenesis of abdominal aortic aneurysm.
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| 5. |
- Gredmark, Sara, et al.
(författare)
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Active cytomegalovirus replication in patients with coronary disease
- 2007
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Ingår i: Scandinavian Cardiovascular Journal. - : Informa UK Limited. - 1401-7431 .- 1651-2006. ; 41:4, s. 230-234
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Tidskriftsartikel (refereegranskat)abstract
- Objectives. To study the prevalence of active cytomegalovirus (CMV) infection in patients with stable and unstable conditions of coronary artery disease (CAD). Design. Forty patients with acute coronary syndrome (ACS), 50 patients with stable angina and angiographically verified CAD (SA) and 50 clinically healthy controls were included. Monocytes were isolated from peripheral blood and CMV-RNA expression was determined by a nested RT-PCR assay. CMV IgM and IgG antibodies, interleukin-(IL)-6, IL-10 and CRP were measured in serum. Results. The prevalence of active CMV infection was significantly higher in patients with ACS (15%) and in patients with SA (10%) compared with controls (2%) (p < 0.001). The presence of an active CMV infection was associated with increased serum concentrations of IL-6. Conclusions. Active CMV infection was found to a larger extent in CAD patients than in healthy controls. The data indicate that CAD patients are more susceptible to reactivation of CMV and put new focus on the role of CMV in atherosclerosis.
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| 6. |
- King, Carina, et al.
(författare)
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COVID-19—a very visible pandemic
- 2020
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Ingår i: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 396:10248, s. 15-15
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Tidskriftsartikel (refereegranskat)
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| 7. |
- Leepiyasakulchai, Chaniya, et al.
(författare)
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Infection Rate and Tissue Localization of Murine IL-12p40-Producing Monocyte-Derived CD103(+) Lung Dendritic Cells during Pulmonary Tuberculosis
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:7
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Tidskriftsartikel (refereegranskat)abstract
- Non-hematopoietic cells, including lung epithelial cells, influence host immune responses. By co-culturing primary alveolar epithelial cells and monocytes from naive donor mice, we show that alveolar epithelial cells support monocyte survival and differentiation in vitro, suggesting a role for non-hematopoietic cells in monocyte differentiation during the steady state in vivo. CD103(+) dendritic cells (alpha E-DC) are present at mucosal surfaces. Using a murine primary monocyte adoptive transfer model, we demonstrate that alpha E-DC in the lungs and pulmonary lymph nodes are monocyte-derived during pulmonary tuberculosis. The tissue localization may influence the functional potential of alpha E-DC that accumulate in Mycobacterium tuberculosis-infected lungs. Here, we confirm the localization of alpha E-DC in uninfected mice beneath the bronchial epithelial cell layer and near the vascular wall, and show that alpha E-DC have a similar distribution in the lungs during pulmonary tuberculosis and are detected in the bronchoalveolar lavage fluid from infected mice. Lung DC can be targeted by M. tuberculosis in vivo and play a role in bacterial dissemination to the draining lymph node. In contrast to other DC subsets, only a fraction of lung alpha E-DC are infected with the bacterium. We also show that virulent M. tuberculosis does not significantly alter cell surface expression levels of MHC class II on infected cells in vivo and that alpha E-DC contain the highest frequency of IL-12p40(+) cells among the myeloid cell subsets in infected lungs. Our results support a model in which inflammatory monocytes are recruited into the M. tuberculosis-infected lung tissue and, depending on which non-hematopoietic cells they interact with, differentiate along different paths to give rise to multiple monocyte-derived cells, including DC with a distinctive alpha E-DC phenotype.
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| 8. |
- Merchut-Maya, Joanna Maria, et al.
(författare)
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Human cytomegalovirus hijacks host stress response fueling replication stress and genome instability
- 2022
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Ingår i: Cell Death and Differentiation. - : Springer Science and Business Media LLC. - 1350-9047 .- 1476-5403. ; 29:8, s. 1639-1653
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Tidskriftsartikel (refereegranskat)abstract
- Viral infections enhance cancer risk and threaten host genome integrity. Although human cytomegalovirus (HCMV) proteins have been detected in a wide spectrum of human malignancies and HCMV infections have been implicated in tumorigenesis, the underlying mechanisms remain poorly understood. Here, we employed a range of experimental approaches, including single-molecule DNA fiber analysis, and showed that infection by any of the four commonly used HCMV strains: AD169, Towne, TB40E or VR1814 induced replication stress (RS), as documented by host-cell replication fork asymmetry and formation of 53BP1 foci. The HCMV-evoked RS triggered an ensuing host DNA damage response (DDR) and chromosomal instability in both permissive and non-permissive human cells, the latter being particularly relevant in the context of tumorigenesis, as such cells can survive and proliferate after HCMV infection. The viral major immediate early enhancer and promoter (MIEP) that controls expression of the viral genes IE72 (IE-1) and IE86 (IE-2), contains transcription-factor binding sites shared by promoters of cellular stress-response genes. We found that DNA damaging insults, including those relevant for cancer therapy, enhanced IE72/86 expression. Thus, MIEP has been evolutionary shaped to exploit host DDR. Ectopically expressed IE72 and IE86 also induced RS and increased genomic instability. Of clinical relevance, we show that undergoing standard-of-care genotoxic radio-chemotherapy in patients with HCMV-positive glioblastomas correlated with elevated HCMV protein markers after tumor recurrence. Collectively, these results are consistent with our proposed concept of HCMV hijacking transcription-factor binding sites shared with host stress-response genes. We present a model to explain the potential oncomodulatory effects of HCMV infections through enhanced replication stress, subverted DNA damage response and induced genomic instability.
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| 9. |
- Ohlin, Mats, et al.
(författare)
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Human antibody technology and the development of antibodies against cytomegalovirus.
- 2015
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Ingår i: Molecular Immunology. - : Elsevier BV. - 1872-9142 .- 0161-5890. ; 67:2, s. 153-170
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Forskningsöversikt (refereegranskat)abstract
- Cytomegalovirus (CMV) is a virus that causes chronic infections in a large set of the population. It may cause severe disease in immunocompromised individuals, is linked to immunosenescence and implied to play an important role in the pathogenesis of cardiovascular diseases and cancer. Modulation of the immune system's abilities to manage the virus represent a highly viable therapeutic option and passive immunotherapy with polyclonal antibody preparations is already in clinical use. Defined monoclonal antibodies offer many advantages over polyclonal antibodies purified from serum. Human CMV-specific monoclonal antibodies have consequently been thoroughly investigated with respect to their potential in the treatment of diseases caused by CMV. Recent advances in human antibody technology have substantially expanded the breadth of antibodies for such applications. This review summarizes the fundamental basis for treating CMV disease by use of antibodies, the basic technologies to be used to develop such antibodies, and relevant human antibody specificities available to target this virus.
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| 10. |
- Olofsson, Peder, et al.
(författare)
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The antiviral cytomegalovirus inducible gene 5/viperin is expressed in atherosclerosis and regulated by proinflammatory agents
- 2005
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : American Heart Association. - 1079-5642 .- 1524-4636. ; 25:7, s. 113-116
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:Inflammatory processes play an important role in atherosclerosis, and increasing evidence implies that microbial pathogens and proinflammatory cytokines are involved in the development and activation of atherosclerotic lesions. To find new inflammatory genes, we explored the vascular transcriptional response to an activator of innate immunity bacterial lipopolysaccharides (LPSs).METHODS AND RESULTS:Gene arrays identified the cytomegalovirus-inducible gene 5 (cig5)/viperin among the genes most potently induced by LPS in human vascular biopsies. Viperin was expressed by endothelial cells in atherosclerotic arteries and significantly elevated in atherosclerotic compared with normal arteries. In culture, cytomegalovirus infection, interferon-gamma, and LPS induced viperin expression.CONCLUSIONS:Viperin is expressed in atherosclerosis and induced in vascular cells by inflammatory stimuli and cytomegalovirus infection. The putative functions of viperin in atherosclerosis may relate to disease-associated microbes.
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