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ZusammenfassungBakterielle zoonotische Erreger sind häufig Auslöser von Erkrankungen mit teilweise schweren Verläufen. Sie sind wechselseitig zwischen Tieren (sowohl Wild- als auch Haustieren) und Menschen übertragbar. Die Transmissionswege sind sehr variabel, so kann die Übertragung u. a. durch orale Aufnahme über Lebensmittel, respiratorische Aufnahme über Tröpfchen und Aerosole sowie über Vektoren wie Zeckenstiche oder Nagerkontakte stattfinden. In diesem Zusammenhang sind auch das Auftreten und die Verbreitung von antibiotikaresistenten bakteriellen Erregern von zunehmender Bedeutung für den öffentlichen Gesundheitsschutz.Die Ausbreitung zoonotischer Erreger wird aktuell durch zahlreiche Faktoren verstärkt. Dazu gehören die Zunahme des internationalen Warenverkehrs, die Einengung der Lebensräume von Tieren und der dadurch zunehmend engere Kontakt zwischen Menschen und Wildtieren. Aber auch eine veränderte Tierhaltung in der Landwirtschaft und Klimaveränderungen können zur Ausbreitung beitragen. Der öffentliche Gesundheitsschutz und die Erforschung von Zoonosen sind deshalb von besonderer krankheitspräventiver, aber auch gesellschaftlicher, politischer und wirtschaftlicher Bedeutung.Ziel dieses Übersichtsartikels ist es, anhand von Beispielen die Spannbreite von Infektionskrankheiten darzustellen, die durch bakterielle zoonotische Erreger ausgelöst werden. Die unterschiedlichen Transmissionswege, epidemischen Potenziale und epidemiologischen Maßzahlen der beispielhaft gewählten Krankheiten sind Herausforderungen für den öffentlichen Gesundheitsdienst, den Tiergesundheitsdienst und die Lebensmittelüberwachung, deren Aufgabe es ist, die Bevölkerung vor diesen Infektionskrankheiten zu schützen.

West Nile virus (WNV) is an arthropod-borne virus (arbovirus). It circulates in an enzootic cycle between ornithophilic mosquitoes as vectors and reservoirs and avian host species for amplification, but humans can be infected as accidental hosts. In most individuals, WNV infection remains silent, while 20% develop mild symptoms of West Nile fever, and only 1% develop neuroinvasive disease (WNND). Human WNV cases have been identified in Southern and Eastern Europe for more than 20 years, but until 2018, Germany was considered to be a non-endemic country. This changed when in the exceptionally warm summer of 2018, conditions for viral replication in mosquitoes were ideal, and the first WNV cases among birds and horses were identified. The widespread domestic Culexmosquitoes are efficient vectors for WNV. Autochthonous mosquito-borne WNV infections in humans were reported in all following years, indicating a continuous circulation in the affected areas of Central-East Germany. So far, no clear expansion of the affected areas is discernible but may develop. WNV is a transfusion-transmissible-infection, and donor deferral or testing of donations after a stay in an affected area are effective means to ensure transfusion safety. WNV transmissions via blood products often result in WNND due to the predisposing underlying medical conditions of transfusion recipients. From 2020 onwards, roughly 80% of all blood establishments in Germany tested their donations for WNV using nucleic acid amplification techniques in the transmission season. Altogether, 19 confirmed WNV infections were identified from 2020–2021. As long as effective and affordable pathogen reduction is not available for all blood components, WNV testing or donor deferral will be essential. In order to timely identify affected areas, combined results of human and veterinary surveillance are needed. Partnerships between public health experts, transfusion medicine specialists, veterinarians, and entomologists should be strengthened to ensure a One Health approach.

We used 10 years of surveillance data to describe listeriosis frequency in Germany. Altogether, 5,576 cases were reported, 91% not pregnancy associated; case counts increased over time. Case-fatality rate was 13% in non-pregnancy-associated cases, most in adults ≥65 years of age. Detecting, investigating, and ending outbreaks might have the greatest effect on incidence.

To validate anecdotal evidence on scabies infestations, we analyzed inpatient and outpatient claims data in Germany. Scabies diagnoses increased 9-fold and treatment failure 4-fold during 2009–2018, driven mainly by persons 15–24 years of age. Prevention and control in young adults appear key because of these persons’ high mobility and social connectivity.

By 22 June 2022, 521 cases of monkeypox were notified in Germany. The median age was 38 years (IQR: 32–44); all cases were men. In Berlin, where 69% of all cases occurred, almost all were men who have sex with men. Monkeypox virus likely circulated unrecognised in Berlin before early May. Since mid-May, we observed a shift from travel-associated infections to mainly autochthonous transmission that predominantly took place in Berlin, often in association with visits to clubs and parties.

An extensive multi-country outbreak of multidrug-resistant monophasic

Zusammenfassung Ziel der Studie Die alveoläre Echinokokkose (AE) ist in Österreich, der Schweiz und Deutschland (DACh) eine seltene Erkrankung, welche durch eine Infektion mit dem Parasiten Echinococcus multilocularis hervorgerufen werden kann. Ziel der Arbeit ist die Darstellung von Unterschieden im Erfassungs- und Meldesystem der alveolären Echinokokkose in Österreich, der Schweiz und Deutschland und der Beschreibung der epidemiologischen Entwicklungen und deren Trends. Methodik Im Rahmen eines Epidemiologischen Updates am 06. September 2019 in Ulm, Deutschland diskutierten Experten und Repräsentanten über Unterschiede im Melde- und Erfassungssystem sowie über die aktuelle epidemiologische Situation. Ergebnisse In Österreich besteht seit 2004 nach §1 Abs. 1 eine namentliche Meldepflicht nach dem Epidemiegesetz 1950 (EpidemieG) und der Verordnung gemäß der anzeigepflichtig übertragbarer Krankheiten für Verdachts-, Erkrankungs- und Todesfälle für eine alveoläre Echinokokkose. Nach §7 Abs. 3 Infektionsschutzgesetz (IfSG) besteht für Deutschland seit 2001 ebenfalls eine Meldepflicht, allerdings nichtnamentlich. Zusätzlich stehen in beiden Ländern nationale Register bereit, welche für die Beantwortung wissenschaftlicher Fragen genutzt werden können. In der Schweiz besteht seit 1997 keine Meldepflicht mehr für die humane alveoläre Echinokokkose. Derzeit bestehen Bestrebungen für die zeitnahe Implementierung eines nationalen Registers für die alveoläre Echinokokkose in der Schweiz. Trotz unterschiedlicher Melde- und Erfassungssysteme zeigt sich für DACh ein ähnlicher epidemiologischer Trend. Schlussfolgerungen In Österreich, der Schweiz und Deutschland zeigt sich ein leicht steigender Trend von humanen Erkrankungsfällen mit alveolärer Echinokokkose. Die direkte Vergleichbarkeit ist aufgrund unterschiedlicher Meldepflichten und deren Strukturen eingeschränkt und erlaubt häufig nicht die gemeinschaftliche Beantwortung wissenschaftlicher Fragestellungen zur Diagnostik, Behandlung und Versorgung.

Background Healthcare-associated foodborne outbreaks (HA-FBO) may have severe consequences, especially in vulnerable groups. Aim The aim was to describe the current state of HA-FBO and propose public health recommendations for prevention. Methods We searched PubMed, the Outbreak Database (Charité, University Medicine Berlin), and hand-searched reference lists for HA-FBO with outbreak onset between 2001 and 2018 from Organisation for Economic Co-operation and Development (OECD) countries and HA-FBO (2012–2018) from the German surveillance system. Additionally, data from the European Food Safety Authority were analysed. Results The literature search retrieved 57 HA-FBO from 16 OECD countries, primarily in the US (n = 11), Germany (n = 11) and the United Kingdom (n = 9). In addition, 28 HA-FBO were retrieved from the German surveillance system. Based on the number of outbreaks, the top three pathogens associated with the overall 85 HA-FBO were Salmonella (n = 24), norovirus (n = 22) and Listeria monocytogenes (n = 19). Based on the number of deaths, L. monocytogenes was the main pathogen causing HA-FBO. Frequently reported implicated foods were ‘mixed foods’ (n = 16), ‘vegetables and fruits’ (n = 15) and ‘meat and meat products’ (n = 10). Consumption of high-risk food by vulnerable patients, inadequate time-temperature control, insufficient kitchen hygiene and food hygiene and carriers of pathogens among food handlers were reported as reasons for HA-FBO. Conclusion To prevent HA-FBO, the supply of high-risk food to vulnerable people should be avoided. Well working outbreak surveillance facilitates early detection and requires close interdisciplinary collaboration and exchange of information between hospitals, food safety and public health authorities.

Since January 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread to become a global pandemic [1]. Active case finding, early detection and isolation of cases and their contacts are essential for breaking transmission chains. A modelling study showed that 70% of contacts should be traced in order to control the outbreak, assuming a baseline reproduction rate of 2.5 [2]. Early warning systems for the serious cross-border spread of infectious pathogens include the International Health Regulations (IHR) 2005 and the Early Warning and Response System (EWRS) for the European Union/European Economic Area (EU/EEA) countries [3,4]. Within Germany, communication channels have been established in accordance with the German Infection Protection Act (Infektionsschutzgesetz; IfSG). Cross-border contact tracing at the national level is operated by the Robert Koch Institute (RKI), the federal public health institute in Germany. The first cases of coronavirus disease 2019 (COVID-19) in Germany occurred in Bavaria at the end of January 2020 [5]. The first SARS-CoV-2 cluster also led to cross-border contacts and exposures on flights since close contacts and suspected cases travelled to Austria and Spain after exposure. This required intensive international communication to identify and share the information on contacts with the responsible health authorities. An international communication and contact tracing team (RKI IC-Team) was rapidly created in the RKI COVID-19 Emergency Operations Centre (EOC) including members of all units of the department for infectious disease epidemiology and other departments at the RKI. The core task of the team was to collect and communicate information on confirmed COVID-19 cases and their contacts to other countries in the event of cross-border relevance. In addition, incoming information on German citizens exposed abroad was communicated through the federal state health authorities to the responsible local health authorities in Germany. The spread of SARS-CoV-2 in Germany triggered the introduction of various measures: (i) mass gatherings with more than 1,000 participants were banned after calendar week 10, (ii) schools and public places were closed in several federal states, (iii) physical distancing measures of at least 1.5 m to another person were recommended, (iv) it was recommended to cancel non-essential travel and (v) quarantine measures for travellers from high risk areas entering Germany were introduced in calendar week 15. Because of the federal structure in Germany, the measures and their implementation varied between the states. This work aimed to describe the extent and course of activities resulting from information on COVID-19 exposure events with a cross-border context. Further, we discuss the challenges experienced and possible workflow improvements.

Alveolar echinococcosis (AE) is a rare disease in Austria, Switzerland and Germany (DACh) caused by an infection with the parasite Echinococcus multilocularis. The aim of the study was to describe differences in the detection and reporting systems of alveolar echinococcosis in Austria, Switzerland and Germany and to describe epidemiological trends. As part of an epidemiological update on 6 Since 2004, Austria has had an obligation to report suspected cases, diseases and deaths of alveolar echinococcosis by name in accordance with §1 Para. 1 of the Epidemiegesetz 1950 (EpidemieG) and the Ordinance on Notifiable Communicable Diseases. According to §7 Para. 3 of the German Infection Protection Act (IfSG), Germany has also been subject to a reporting obligation since 2001, but not by name. In addition, national registers are available in both countries, which can be used to answer scientific questions. In Switzerland, there is no obligation to report human alveolar echinococcosis since 1997. Efforts are currently being made to implement a national register for alveolar echinococcosis in Switzerland. Despite different reporting and recording systems, a similar epidemiological trend can be observed for DACh. In Austria, Switzerland and Germany there is a slightly increasing trend of human cases with alveolar echinococcosis. The direct comparability is limited due to different reporting obligations. The structures often do not allow a joint answering of scientific questions concerning diagnostics, treatment and care.Die alveoläre Echinokokkose (AE) ist in Österreich, der Schweiz und Deutschland (DACh) eine seltene Erkrankung, welche durch eine Infektion mit dem Parasiten Echinococcus multilocularis hervorgerufen werden kann. Ziel der Arbeit ist die Darstellung von Unterschieden im Erfassungs- und Meldesystem der alveolären Echinokokkose in Österreich, der Schweiz und Deutschland und der Beschreibung der epidemiologischen Entwicklungen und deren Trends.Im Rahmen eines Epidemiologischen Updates am 06. September 2019 in Ulm, Deutschland diskutierten Experten und Repräsentanten über Unterschiede im Melde- und Erfassungssystem sowie über die aktuelle epidemiologische Situation.In Österreich besteht seit 2004 nach §1 Abs. 1 eine namentliche Meldepflicht nach dem Epidemiegesetz 1950 (EpidemieG) und der Verordnung gemäß der anzeigepflichtig übertragbarer Krankheiten für Verdachts-, Erkrankungs- und Todesfälle für eine alveoläre Echinokokkose. Nach §7 Abs. 3 Infektionsschutzgesetz (IfSG) besteht für Deutschland seit 2001 ebenfalls eine Meldepflicht, allerdings nichtnamentlich. Zusätzlich stehen in beiden Ländern nationale Register bereit, welche für die Beantwortung wissenschaftlicher Fragen genutzt werden können. In der Schweiz besteht seit 1997 keine Meldepflicht mehr für die humane alveoläre Echinokokkose. Derzeit bestehen Bestrebungen für die zeitnahe Implementierung eines nationalen Registers für die alveoläre Echinokokkose in der Schweiz. Trotz unterschiedlicher Melde- und Erfassungssysteme zeigt sich für DACh ein ähnlicher epidemiologischer Trend.In Österreich, der Schweiz und Deutschland zeigt sich ein leicht steigender Trend von humanen Erkrankungsfällen mit alveolärer Echinokokkose. Die direkte Vergleichbarkeit ist aufgrund unterschiedlicher Meldepflichten und deren Strukturen eingeschränkt und erlaubt häufig nicht die gemeinschaftliche Beantwortung wissenschaftlicher Fragestellungen zur Diagnostik, Behandlung und Versorgung.

Objectives Invasive listeriosis is a severe foodborne infection caused by Listeria (L.) monocytogenes. The aim of this investigation was to verify and describe a molecular cluster of listeriosis patients and identify factors leading to this outbreak. Methods Whole genome sequencing and core genome multilocus sequence typing were used for subtyping L. monocytogenes isolates from listeriosis cases and food samples in Germany. Patient interviews and investigational tracing of foodstuffs offered in health-care facilities (HCF), where some of the cases occurred, were conducted. Results We identified a German-wide listeriosis outbreak with 39 genetically related cases occurring between 2014 and 2019. Three patients died as a result of listeriosis. After identification of HCF in different regions of Germany for at least 13 cases as places of exposure, investigational tracing of food supplies in six prioritized HCF revealed meat products from one company (X) as a commonality. Subsequently the outbreak strain was analysed in six isolates from ready-to-eat meat products and one isolate from the production environment of company X. No further Sigma1 cases were detected after recall of the meat products from the market and closure of company X (as of August 2020). Conclusions Interdisciplinary efforts including whole genome sequencing, epidemiological investigations in patients and investigational tracing of foods were essential to identify the source of infections, and thereby prevent further illnesses and deaths. This outbreak underlines the vulnerability of hospitalized patients for foodborne diseases, such as listeriosis. Food producers and HCF should minimize the risk of microbiological hazards when producing, selecting and preparing food for patients.

One year after the first autochthonous transmission of West Nile virus (WNV) to birds and horses in Germany, an epizootic emergence of WNV was again observed in 2019. The number of infected birds and horses was considerably higher compared to 2018 (12 birds, two horses), resulting in the observation of the first WNV epidemy in Germany: 76 cases in birds, 36 in horses and five confirmed mosquito-borne, autochthonous human cases. We demonstrated that Germany experienced several WNV introduction events and that strains of a distinct group (Eastern German WNV clade), which was introduced to Germany as a single introduction event, dominated mosquito, birds, horse and human-related virus variants in 2018 and 2019. Virus strains in this clade are characterized by a specific-Lys2114Arg mutation, which might lead to an increase in viral fitness. Extraordinary high temperatures in 2018/2019 allowed a low extrinsic incubation period (EIP), which drove the epizootic emergence and, in the end, most likely triggered the 2019 epidemic. Spatiotemporal EIP values correlated with the geographical WNV incidence. This study highlights the risk of a further spread in Germany in the next years with additional human WNV infections. Thus, surveillance of birds is essential to provide an early epidemic warning and thus, initiate targeted control measures.

In June 2017, an outbreak of Salmonella Kottbus infection was suspected in Germany. We investigated the outbreak with whole-genome sequencing (WGS) and a case–control study. Forty-six isolates from 69 cases were subtyped. Three WGS clusters were identified: cluster 1 (n = 36), cluster 2 (n = 5) and cluster 3 (n = 3). Compared to controls, cluster 1 cases more frequently consumed raw smoked ham (odds ratio (OR) 10, 95% confidence interval (CI) 1.2–88) bought at supermarket chain X (OR 36, 95% CI 4–356; 9/10 consumed ham Y). All four cluster 2 cases interviewed had consumed quail eggs. Timely WGS was invaluable in distinguishing concurrent outbreaks of a rare Salmonella serotype.

The advancing age of the participants of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study was the incentive to investigate frailty as a major parameter of ageing. The aim of this study was to develop a multidimensional tool to measure frailty in an ageing, free-living study population. The "accumulation of deficits approach" was used to develop a frailty index (FI) to characterize a sub-sample (N = 815) of the EPIC-Potsdam (EPIC-P) study population regarding the aging phenomenon. The EPIC-P frailty index (EPIC-P-FI) included 32 variables from the following domains: health, physical ability, psychosocial and physiological aspects. P-values were calculated for the linear trend between sociodemographic and life style variables and the EPIC-P-FI was calculated using regression analysis adjusted for age. The relationship between the EPIC-P-FI and age was investigated using fractional polynomials. Some characteristics such as age, education, time spent watching TV, cycling and a biomarker of inflammation (C-reactive protein) were associated with frailty in men and women. Interestingly, living alone, having no partner and smoking status were only associated with frailty in men, and alcohol use and physical fitness (VO2max) only in women. The generated, multidimensional FI, adapted to the EPIC-P study, showed that this cohort is a valuable source for further exploration of factors that promote healthy ageing.

Background: Infection with cytomegalovirus (CMV) remains asymptomatic in most immunocompetent hosts, but is the leading cause of congenital viral infection worldwide and can be life-threatening in immunocompromised individuals. We aimed to assess CMV seroprevalence in a nationally representative sample of adults in Germany and to identify sociodemographic factors associated with CMV seropositivity. Methods: Blood samples from 6552 participants (18–79 years) of the “German National Health Interview and Examination Survey 1998”, a population-based sample of the adult population in Germany, were tested for the presence of CMV antibodies using an Ig-multiplex assay. Weighted seroprevalence was calculated and weighted binomial regression was used to identify factors associated with CMV seropositivity. Results: Overall CMV seroprevalence was 56.7% (95%CI: 54.8–58.7%), with a higher seroprevalence in women (62.3%) than in men (51.0%). Seroprevalence increased with age: from 31.8% to 63.7% in men and from 44.1% to 77.6% in women when comparing the 18–29 with the 70–79 year age-group, respectively. CMV seroprevalence in women of childbearing age (18–45 years) was 51.7%. Factors significantly associated with CMV seropositivity were age, country of birth, smoking status, education, living in northern Germany and number of household members. In addition, having attended child care was associated with seropositivity in men, and number of siblings and living in East Germany in women. Conclusion: Our results indicate that half the women of childbearing age were susceptible for primary CMV infection during pregnancy. CMV screening during pregnancy and informing seronegative women about CMV risk reduction measures could prevent congenital CMV infections with its serious consequences.

Alzheimer's disease and dementia with Lewy bodies are the most common neurodegenerative dementias in old age. Accurate diagnosis of these conditions has important clinical implications because they tend to be confounded. In the brain of Alzheimer's disease patients amyloid-beta is produced in excess and deposited as plaques, forming the hallmark of this condition. Lymphocytes have been implicated in the process of amyloid-beta removal and inflammation occurrence. Here we investigated peripheral amyloid-beta1-42-specific T-cells by multicolor flow cytometry to simultaneously detect and characterize activation markers and cell signaling proteins (phospho-protein kinase C) in patients with Alzheimer's disease or Lewy body dementia and in healthy controls. Results indicate that only Alzheimer's disease patients display small subsets of peripheral amyloid-beta1-42-specific T-cells, characterized by bright expression of phosphorylated-protein kinase C-delta or -zeta whose significance although discussed, is far from being understood. The identification of such subsets, anyhow, may strongly contribute to distinguish Alzheimer's disease from dementia with Lewy bodies, opening possible new routes to early therapeutic strategies.

Cytomegalovirus (CMV) -specific immunity is often estimated by the number of in vitro CMV antigen-inducible interferon-gamma-positive (IFN-gamma(+) ) T cells. However, recent work indicates that simultaneous production of IFN-gamma, tumour necrosis factor-alpha (TNF-alpha) and interleukin-2 (IL-2) (referred to as 'polyfunctionality') is more relevant for anti-viral protection. Here, we compared polyfunctionality of CMV-specific T cells (pp65 and IE-1 proteins) in 23 solid-organ transplant patients and seven healthy controls by flow cytometry. The proportions of TNF-alpha(+) /IFN-gamma(+) /IL-2 cells among the activated cells were significantly reduced in transplant patients but not the frequencies of IFN-gamma(+) CD8(+) T cells. Immunosuppression reduces polyfunctionality, which reflects the increased infection risk in this patient group.

P>The relative roles that ageing and lifelong cytomegalovirus (CMV) infection have in shaping naive and memory CD4+ T-cell repertoires in healthy older people is unclear. Using multiple linear regression analysis we found that age itself is a stronger predictor than CMV seropositivity for the decrease in CD45RA+ CD27+ CD4+ T cells over time. In contrast, the increase in CD45RA- CD27- and CD45RA+ CD27- CD4+ T cells is almost exclusively the result of CMV seropositivity, with age alone having no significant effect. Furthermore, the majority of the CD45RA- CD27- and CD45RA+ CD27- CD4+ T cells in CMV-seropositive donors are specific for this virus. CD45RA+ CD27- CD4+ T cells have significantly reduced CD28, interleukin-7 receptor alpha (IL-7R alpha) and Bcl-2 expression, Akt (ser473) phosphorylation and reduced ability to survive after T-cell receptor activation compared with the other T-cell subsets in the same donors. Despite this, the CD45RA+ CD27- subset is as multifunctional as the CD45RA- CD27+ and CD45RA- CD27- CD4+ T-cell subsets, indicating that they are not an exhausted population. In addition, CD45RA+ CD27- CD4+ T cells have cytotoxic potential as they express high levels of granzyme B and perforin. CD4+ memory T cells re-expressing CD45RA can be generated from the CD45RA- CD27+ population by the addition of IL-7 and during this process these cells down-regulated expression of IL-7R and Bcl-2 and so resemble their counterparts in vivo. Finally we showed that the proportion of CD45RA+ CD27- CD4+ T cells of multiple specificities was significantly higher in the bone marrow than the blood of the same individuals, suggesting that this may be a site where these cells are generated.

Multi-colour flow cytometry is the only technological platform that can analyse the highly complex cellular composition of the immune system in parallel and at single cell resolution. Analysis of the T cell compartment, in particular, requires the simultaneous measurement of multiple markers in order to account for lineage, phenotype and function. Flow cytometry also enables the analysis of intracellular signalling events. By combining the expression of surface markers, intracellular cytokines, phosphorylated versus unphosphorylated kinases, cell proliferation and DNA profile, mechanistic and kinetic information of subset-specific signalling may be obtained: this has not previously been achieved. Here we present a protocol which permits all of these aspects to be explored simultaneously. By comparing basic procedures previously described we were able to optimise different variables, including the choice of antibody/fluorochrome pairs, permeabilisation, fixation and labelling time, to obtain the best DNA staining of different cell types. We applied this method to study subset-specific signalling related to cytokine production and DNA synthesis in T cells responding to specific antigens.

Objectives: To determine if there is a biological mechanism that explains the association between HIV disease progression and increased mortality with low circulating vitamin D levels; specifically, to determine if restoring vitamin D levels induced T-cell functional changes important for antiviral immunity. Design: This was a pilot, open-label, three-arm prospective phase 1 study. Methods: We recruited 28 patients with low plasma vitamin D (75 nmol/l) in 27 of 28 patients, with no safety issues. The most striking change was in HIV+ HAART+ patients, where increased frequencies of antigen-specific T cells expressing macrophage inflammatory protein (MIP)-1β – an important anti-HIV blocking chemokine – were observed, with a concomitant increase in plasma MIP-1β, both of which correlated significantly with vitamin D levels. In addition, plasma cathelicidin – a vitamin D response gene with broad antimicrobial activity – was enhanced. Conclusion: Vitamin D supplementation modulates disease-relevant T-cell functions in HIV-infected patients, and may represent a useful adjunct to HAART therapy.

Large cytomegalovirus (CMV)-specific CD8 T-cell responses are observed in both young and, somewhat more often, old people. Frequent CMV reactivation is thought to exhaust these cells and render them dysfunctional so that larger numbers of them are needed to control CMV. Expansions of CMV-specific CD4 T cells are also seen but are less well studied. In this study, we examined the T-cell response to the dominant CMV pp65 and IE-1 antigens in healthy CMV-infected people across a wide age range (20 to 84 years) by using multicolor flow cytometry. CMV-specific T cells were characterized by the activation markers CD40 ligand (CD40L), interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ) and the memory markers CD27 and CD45RA. The proportions of effector memory T cells increased in large responses, as did the proportions of polyfunctional CD8 (IFN-γ + IL-2 +/− TNF-α + ) and CD4 (CD40L +/− IFN-γ + IL-2 + TNF-α + ) T-cell subsets, while the proportion of naïve T cells decreased. The bigger the CD4 or CD8 T-cell response to pp65, the larger was the proportion of T cells with an advanced memory phenotype in the entire (including non-CMV-specific) T-cell compartment. In addition, the number of activation markers per cell correlated with the degree of T-cell receptor downregulation, suggesting increased antigen sensitivity in polyfunctional cells. In summary, our findings show that polyfunctional CMV-specific T cells were not superseded by dysfunctional cells, even in very large responses. At the same time, however, the memory subset composition of the entire T-cell compartment correlated with the size of the T-cell response to CMV pp65, confirming a strong effect of CMV infection on the immune systems of some, but not all, infected people.

Despite the success of antivirals in preventing clinically overt CMV disease in cardiac allograft recipients, sub-clinical active CMV infection remains a major concern because of its association with allograft rejection and vasculopathy. The measurement of CMV specific T-cell responses is a promising approach to assessing this situation. For simplicity, class-1 MHC/peptide-multimers staining CD8 T-cells directly are often used but this ignores a much wider range of responses including the whole CD4 T-cell compartment. CD4 T-cells, however, were recently shown to be critical to reducing CMV load early after transplantation. To determine how extensive T-cell responses to CMV are, the responses to two dominant CMV proteins, IE-1 and pp65, were dissected in detail accounting for T-cell lineage, frequencies, epitope recognition and changes over time in more than 25 heart transplant recipients. Cross-sectional results from over 30 healthy CMV-carriers were analyzed for comparison. Responses were unexpectedly complex, with considerable inter-individual variation in terms of dominance, breadth, and recognized epitopes. Whereas the use of MHC/peptide-multimers for clinical CD8 T-cell response monitoring alone can be justified in some situations, short term T-cell activation combined with intracellular cytokine staining was clearly found to be of more general usefulness. The performance of IFN-gamma, TNF-alpha, or IL-2 as single read-outs in identifying activated T-cells was examined and confirmed that the frequently used IFN-gamma was best suited. These results should be used to inform the design of clinically applicable and diagnostically useful approaches to monitoring CMV specific responses in heart transplant recipients.