Manipulation of NKG2D Ligands by Cytomegaloviruses: Impact on Innate and Adaptive Immune Response

NKG2D is a potent activating receptor expressed on NK cells, NKT cells, γδ T cells, and CD8 T cells. NKG2D recognizes cell surface molecules structurally related to MHC class I proteins induced by infection or other type of cellular stress. The engagement of NKG2D leads to NK cell cytotoxicity and cytokine secretion or to a co-stimulation of CD8 T cells. Both human and mouse cytomegalovirus (CMV) have evolved numerous mechanisms to evade NKG2D-mediated immune response. This review describes the mechanisms used by CMV to inhibit NKG2D ligand expression and the recent advances in exploiting the NKG2D recognition pathway for mounting efficient and long-lasting immune response

New Epidemiological Fetures of Hepatitis A - Experience of the Clinical Centre Rijeka in the Past Twelve-Year Period

Cilj: Incidencija hepatitisa A u našoj zemlji, slično ostalim razvijenim zemljama, niska je zahvaljujući poboljšanju socioekonomskog standarda i higijenskih uvjeta. U razvijenim zemljama svijeta posljednje desetljeće opisane su epidemije hepatitisa A vezane uz „novi”, spolni put prijenosa, poglavito u MSM populaciji (engl. Men Sex Men; MSM) i u osoba s drugim spolno prenosivim infekcijama. Budući da u razvijenim zemljama od hepatitisa A češće obolijevaju osobe odrasle dobi, učestalost komplikacija veća je u odnosu na nerazvijene zemlje gdje je hepatitis A bolest dječje dobi, što je poznato kao „paradoksalni rizik”. Svrha je ovog rada opisati epidemiološke osobitosti i kliničku sliku bolesnika s hepatitisom A u proteklom dvanaestogodišnjem razdoblju. Ispitanici i metode: Istraživanjem je obuhvaćen 21 bolesnik s hepatitisom A liječen u Klinici za infektivne bolesti Kliničkog bolničkog centra Rijeka u razdoblju od 2010. do 2021. godine. Rezultati: Najveći dio oboljelih osoba bio je srednje životne dobi (40 - 49 godina). U razdoblju do 2010. do 2016. godine liječen je 0 - 1 bolesnik s hepatitisom A godišnje, dok je 2017. i 2018. godine liječeno 16 bolesnika i 2019. dva bolesnika. Godine 2020. i 2021., u vrijeme epidemije COVID-19, nismo liječili oboljele od hepatitisa A. Većinu oboljelih činili su muškarci. Uz fekooralni put prijenosa glavni put prijenosa infekcije bio je spolni put u MSM populaciji. Tijek bolesti bio je blag. Zaključci: Epidemiološke značajke bolesnika s hepatitisom A obuhvaćenih studijom zrcale nove epidemiološke trendove hepatitisa A u razvijenim europskim zemljama - s najvećim brojem oboljelih u odrasloj dobi i „novim”, spolnim putem prijenosa infekcije.Aim: Incidence of hepatitis A in our country, like other developed countries, is low due to the improvement of socioeconomic and hygienic standards. However, in the last decade epidemics of hepatitis A related to the "new" sexual route of transmission have been described, mainly in the Men Sex Men (MSM) population. Since in the developed countries hepatitis A occurs more commonly in adults, the frequency of complications is higher compared to underdeveloped countries known as "paradoxical risk". The aim is to characterize current epidemiological features and clinical presentation of hepatitis A infection. Patients and methods: A retrospective study was conducted in the Clinic for Infectious Diseases, University Hospital Centre Rijeka from 2010 to 2021 and included 21 patients with hepatitis A. Results: The age range of patients was six to 70 years, and most patients were middle-aged (40 - 49 years). In the period from 2010 to 2016, 0 - 1 patients with hepatitis A were treated annually while in 2017 and 2018 16 patients were treated, mostly man. Two patients were treated in 2019. while in 2020 and 2021, during COVID-19 pandemic, there were no patients with HAV. In addition to the feco-oral route, the major assumed route of transmission was sexual in MSM population. The course of disease was mild in all patients. Conclusions: Epidemiological characteristics of patients included in the study reflect the new epidemiological trends of hepatitis A in developed countries with most patients being infected in adulthood and the "new" sexual route of transmission

Mycoplasma pneumoniae induced Stevens-Johnson syndrome

Stevens-Johnsonov sindrom (SJS) je teška bolest kože i sluznica karakterizirana target (iris) lezijama i nekrozom epidermisa kao posljedica reakcije preosjetljivosti potaknute lijekovima, infektivnim uzročnicima ili malignomima. Prikazujemo slučaj Stevens-Johnsonova sindroma u mlađeg muškarca potaknutog atipičnom upalom pluća uzrokovanom infekcijom Mycoplasma pneumoniae (M. pneumoniae). Primjena antimikrobne i kratkotrajne sistemske kortikosteroidne terapije uz simptomatske mjere rezultirala je izlječenjem bez zaostajanja trajnih posljedica.Stevens-Johnson syndrome (SJS) is a severe disease of the skin and mucous membranes characterized by target lesions and epidermal necrosis induced by hypersensitivity to medications, infections and malignancies. We present a case of Stevens-Johnson syndrome in a young male secondary to interstitial pneumonia caused by Mycoplasma pneumoniae (M. pneumoniae). Antimicrobial and short course systemic corticosteroid therapy combined with supportive measures resulted in a recovery without any long-term sequelae

Mycoplasma pneumoniae induced Stevens-Johnson syndrome

Stevens-Johnsonov sindrom (SJS) je teška bolest kože i sluznica karakterizirana target (iris) lezijama i nekrozom epidermisa kao posljedica reakcije preosjetljivosti potaknute lijekovima, infektivnim uzročnicima ili malignomima. Prikazujemo slučaj Stevens-Johnsonova sindroma u mlađeg muškarca potaknutog atipičnom upalom pluća uzrokovanom infekcijom Mycoplasma pneumoniae (M. pneumoniae). Primjena antimikrobne i kratkotrajne sistemske kortikosteroidne terapije uz simptomatske mjere rezultirala je izlječenjem bez zaostajanja trajnih posljedica.Stevens-Johnson syndrome (SJS) is a severe disease of the skin and mucous membranes characterized by target lesions and epidermal necrosis induced by hypersensitivity to medications, infections and malignancies. We present a case of Stevens-Johnson syndrome in a young male secondary to interstitial pneumonia caused by Mycoplasma pneumoniae (M. pneumoniae). Antimicrobial and short course systemic corticosteroid therapy combined with supportive measures resulted in a recovery without any long-term sequelae

The Many Faces of Cat Scratch Disease – A Report of Four Cases

Bolest mačjeg ogreba (BMO) infekcija je uzrokovana Gram negativnom, fakultativno intracelularnom bakterijom Bartonella henselae. Glavni rezervoar infekcije je mačka i oko 75% bolesnika ima podatak o ogrebu ili ugrizu mačke u anamnezi. Rjeđe se infekcija javlja u kontaktu s psom, posredovano mačjom buhom ili neizravnim kontaktom oštećene kože ili sluznice s površinom kontaminiranom mačjom slinom. Infekcija može proći asimptomatski, ali se i prezentirati spektrom kliničkih manifestacija. U 85-90 % bolesnika radi se o klasičnoj BMO s kožnom lezijom i samoograničavajućim, regionalnim limfadenitisom dok ostale, rjeđe kliničke manifestacije, mogu zahvatiti gotovo svaki organ i organski sustav. Prikazujemo četiri bolesnika s BMO liječenih u Klinici za infektivne bolesti Kliničkog bolničkog centra Rijeka te raspravljamo o dijagnostičkim i terapijskim izazovima ove bolesti.Cat scratch disease (CSD) is an infection caused by the Gram negative, facultative intracellular bacteria Bartonella henselae. The main reservoir of the infection is cat and about 75% of the patients have a cat scratch or a bite in anamnesis. Rarely, infection results from exposure to dogs, cat fleas or from contact with cat saliva through broken skin or mucosal surfaces. Infection can be asymptomatic or present with a number of clinical manifestations. In wast majority (85-90%) of the patients CSD presents as a cutaneous lesion and self-limiting, regional lymphadenitis near the site of organism inoculation, other seldom manifestations, however, can include virtually every organ and organ system. We present four patients with CSD treated at the Clinical Hospital Center Rijeka and discuss diagnostic and therapeutic challenges of the CSD

Bivalvular Staphylococcus aureus endocarditis in a young pregnant woman without known previous risk factors – a case report

Infektivni endokarditis značajan je uzrok pobola i smrtnosti. Posebno je težak klinički entitet u trudnica s obzirom na određeni stupanj imunosupresije u trudnoći, kao i zbog značajnih promjena kardiovaskularne funkcije u trudnica. Većina infektivnih endokarditisa, pa i u trudnoći, uzrokovana je bakterijama, a dominantno je zahvaćen jedan srčani zalistak, najučestalije mitralnog ušća. U ovom radu je prikazan slučaj liječenja i ishoda endokarditisa mitralnog i aortnog zaliska uzrokovanog bakterijom Staphylococcus aureus u prethodno zdrave trudnice.Infectious endocarditis is a significant cause of morbidity and mortality. It is a particularly difficult clinical entity in pregnant women due to a certain degree of immunosuppression in pregnancy, as well as due to significant changes in cardiovascular function in pregnant women. Most infectious endocarditis cases, even in pregnancy, are caused by bacteria, with one heart valve, most commonly the mitral orifice, predominantly affected. This paper presents treatment and outcome of mitral and aortic valve endocarditis caused by Staphylococcus aureus in a previously healthy pregnant woman

Tick-Borne Encephalitis Due to Consumption of Raw Goat Milk, Gorski kotar, 2019: Clinical Case Reports

Virus krpeljnog meningoencefalitisa (KME) najčešći je uzročnik infekcija središnjeg živčanog sustava u endemskim područjima srednje Europe. Radi se o prirodno žarišnoj zoonozi, čiji rezervoar čine šumski glodavci, domaće i divlje životinje, a čovjek se zarazi prigodno, ubodom inficiranog krpelja. U posljednje je vrijeme sve više izvješća o epidemijama KME povezanih s konzumacijom svježeg mlijeka i mliječnih proizvoda. Cilj je rada prikazati kliničke značajke i tijek bolesti kod oboljelih od KME u tijeku grupiranja u Primorsko- goranskoj županiji (lipanj 2019. godine), povezanog s konzumacijom nepasteriziranog kozjeg mlijeka iz istog izvora. Tri su bolesnika hospitalizirana s kliničkom slikom meningitisa, a kod dvoje se infekcija prezentirala kao febrilna bolest s mijalgijama i općom slabošću. Kod svih je bolesnika infekcija potvrđena serološkom obradom. Niti jedan bolesnik nije bio cijepljen protiv KME niti je imao podatak o ugrizu krpelja. Ovim radom želimo ukazati na zdravstvene opasnosti prehrambenih navika konzumiranja sirovog mlijeka koje u današnje vrijeme postaje sve popularnije, osobito među zagovornicima „zdrave hrane“.Tick-borne encephalitis (TBE) is the most common central nervous system (CNS) infection in the endemic areas of Central Europe. TBE is a zoonosis whose reservoir are forest rodents, and other mammals and vectors are Ixodes ticks. Humans become infected through a tick bite, but recently many TBE outbreaks after consumption of unpasteurized milk and dairy products from infected livestock have been described. The aim of this study was to analyze clinical characteristics of five TBE cases who were infected after consumption of unpasteurized goat milk and dairy products from a small family farm in Primorje-Gorski Kotar County (June 2019). Tree patients developed CNS infection while two had febrile illness. None of the infected patients reported a history of a tick-bite or were vaccinated against TBE. The infection was confirmed by detection of TBE specific antibodies. Since "healthy" lifestyle that encourages consumption of raw milk and dairy products is increasingly fashionable, we would like to point out the importance of pasteurizing or boiling milk before the consumption

Temporal Bone Actinomycosis Accompanied by Actinomycotic Meningitis and Cervical Lymphadenitis – a Case Report

Aktinomikoza predstavlja rijetku kroničnu infekciju uzrokovanu anaerobnom, Gram pozitivnom bakterijom koja pripada rodu Actinomyces. U ovom smo radu prikazali slučaj aktinomikoze temporalne kosti i meningitisa uzrokovanog Aktinomicetama te limfadenitisa vrata kod imunokompetentne bolesnice s anamnezom kroničnog supurativnog otitisa nakon traumatske perforacije bubnjića starijeg datuma. Liječenje je uspješno provedeno kombiniranom kirurškom i dugotrajnom antimikrobnom terapijom. Ovim prikazom želimo skrenuti pozornost na meningitis kojeg uzrokuje Actinomyces spp. te kojeg je, iako je rijedak, potrebno uključiti u diferencijalnu dijagnozu kroničnog meningitisa, osobito kod pacijenata s kroničnom upalom srednjeg uha i paranazalnih sinusa. Jednako tako, želimo skrenuti pozornost i na ostale manifestacije ove rijetke bolesti.Actinomycosis represents rare chronic infection caused by anaerobic, Gram positive bacteria belonging to Actinomyces genus. Here we present a case of temporal bone actinomycosis accompanied by meningitis and cervical lymphadenitis in imunocompetent patient with case history of chronic suppurative otitis media as a tympanic membrane perforation sequelae. The patient was successfully treated with both surgical and prolonged antimicrobial therapy. This case, although rare, implies cosideration of Actinomyces spp. in diferential diagnosis of chronic meningitis, especially in patients with case history of chronic otitis media or chronic sinusitis

The Role of Receptor NKG2D in the Immune Control of the Cytomegalovirus Infection

Cilj istraživanja:Razjasniti ulogu receptora NKG2D u uspostavi i održavanjulatentnecitomegalovirusne (CMV) infekcije,tepoticanjuvirus-specifičnogimunološkog odgovora.Materijali i metode: Miševi suinficirani rekombinantnim sojevima MCMV-a kojima su uklonjeni pojedini imunosubverzivni geni za NKG2D ligande (Δm138 MCMV, Δm145MCMV i Δm152MCMV), rekombinantnim MCMV-om koji izražava NKG2D ligand RAE-1γ(RAE-1γMCMV) ili divljim tipom virusa (WT MCMV). Rast virusa u tkivima je uspoređen testom virusnih čistina, a količina virusnog genoma u krvi itkivima kvantitativnim PCR-om. Kinetika i fenotip virus-specifičnih stanica testirani su protočnom citometrijom. Rezultati: Usprkosrane atenuacije, rekombinantni sojevi MCMV-a kojima su uklonjeni pojedini imunosubverzivni geni za NKG2D ligande pokazuju kasni oporavak rasta u žlijezdama slinovnicama. Količina latentnog virusnog genoma u krvi i tkivima, te kinetika i fenotip virus-specifičnog staničnog i humoralnog imunološkog odgovora nakon infekcije delecijskim mutantama MCMV-a i WT MCMV-om su usporedivi. MCMVkoji izražava NKG2D ligand RAE-1γdrastično je atenuiran in vivoine kolonizira žlijezde slinovnice. Smanjen rastRAE-1γMCMV-a rezultira bržim nestajanjem virusne DNK iz krvi i smanjenom količinom latentnog virusnog genoma u tkivima odraslih, imunokompetentnih miševa i novookoćenih miševa s nedozrelim imunološkim sustavom. Infekcija ovim virusomje uspješno kontrolirana i u imunokompromitiranog domaćina kao što su miševa kojima nedostaje receptor za tip I interferone i u miševa imunokompromitiranih γ-zračenjem. Stanični i humoralni imunološki odgovor potaknut infekcijom RAE-1γMCMV-om usporediv je s onim nakon infekcije WT MCMV-om i štiti domaćina od letalne CMV infekcije. RAE-1γMCMV uspostavlja latencijus mogućnošćureaktivacije virusa u uvjetima imunosupresije. Usprkos snažnog selekcijskog tlaka imunološkog sustavaRAE-1γizražen kao transgen u RAE-1γMCMV genomu ne podliježe mutacijama.Imunizacija mišica RAE-1γMCMV-om štiti njihovumladunčadod CMV bolesti posredovano transplacentarno prenesenim virus-specifičnim protutijelima. IIZaključak: Receptor NKG2D igra važnu ulogu u uspostavi i održavanjulatentne CMV infekcije, te poticanju virus-specifičnog imunološkog odgovora. RekombinantanCMV konstruiran tako da izražava NKG2D ligand RAE-1γ je izvrstan kandidatza sigurnu i učinkovitu CMV vakcinuili vektor za izražaj antigena drugih patogena.Objectives:Of the study are to clarify the role of receptor NKG2D during latent cytomegalovirus (CMV) infection and in the process of priming and maintenance of virus-specific immune response. Materials and methods:Mice were infected with recombinant MCMVs lacking one of the NKG2D imunoevasion genes (Δm138 MCMV, Δm145MCMV and Δm152MCMV), MCMV expressingNKG2D ligand RAE-1γ(RAE-1γMCMV) or wild type MCMV (WT MCMV). Viral titers were determined by virus titration and viral DNA load by quantitative PCR. Kinetics and phenotype of virus-specific lymphocytes were tested by FACS analysis. Results: Despite early attenuation, recombinant MCMVs lacking any of the NKG2D immunovasion genes show late recoveryof infectious virus in salivary glands. Latent virus DNA load as well as kinetics and phenotype of virus-specific immune response after infection withMCMV deletion mutants and WT MCMV are comparable. RAE-1γMCMV is strongly attenuated in vivoand failsto establish persistentinfection in salivary glands. Strong attenuation of RAE-1γMCMV results in faster clearance of virus DNA from blood and significantly lower latent virus DNA load in tissues in adult, immunocompetent mice and in the newborn mice with immature immune system. Despite tight innate immune control RAE-1γMCMV infection elicits strong and enduring antiviral immune response that confersprotection against lethal MCMV infection. Strong attenuation does not prevent RAE-1γMCMV from establishing latency and reactivating upon immunosuppression. Infection with RAE-1γMCMV presentsa low risk for disease even in severely immunodeficient host such as mice lacking receptor for type I interferons and mice immunocompromised by γ-irradiation. In spite of the strong selective pressure by the immune system RAE-1γ remains intact during latent RAE-1γMCMV infection. Maternal RAE-1γMCMV immunization protects neonatal mice from MCMV infection upon placental transfer of antiviral antibodies. IVConclusions: Receptor NKG2D plays a major role during latent CMV infection and in the process of priming and maintenanceof virus-specific immune response. Recombinant CMV designedto expressNKG2D ligand is anexcellent candidate for a safe and immunogenicCMV vaccine or CMV-based vaccine vector

The Role of Receptor NKG2D in the Immune Control of the Cytomegalovirus Infection

Cilj istraživanja:Razjasniti ulogu receptora NKG2D u uspostavi i održavanjulatentnecitomegalovirusne (CMV) infekcije,tepoticanjuvirus-specifičnogimunološkog odgovora.Materijali i metode: Miševi suinficirani rekombinantnim sojevima MCMV-a kojima su uklonjeni pojedini imunosubverzivni geni za NKG2D ligande (Δm138 MCMV, Δm145MCMV i Δm152MCMV), rekombinantnim MCMV-om koji izražava NKG2D ligand RAE-1γ(RAE-1γMCMV) ili divljim tipom virusa (WT MCMV). Rast virusa u tkivima je uspoređen testom virusnih čistina, a količina virusnog genoma u krvi itkivima kvantitativnim PCR-om. Kinetika i fenotip virus-specifičnih stanica testirani su protočnom citometrijom. Rezultati: Usprkosrane atenuacije, rekombinantni sojevi MCMV-a kojima su uklonjeni pojedini imunosubverzivni geni za NKG2D ligande pokazuju kasni oporavak rasta u žlijezdama slinovnicama. Količina latentnog virusnog genoma u krvi i tkivima, te kinetika i fenotip virus-specifičnog staničnog i humoralnog imunološkog odgovora nakon infekcije delecijskim mutantama MCMV-a i WT MCMV-om su usporedivi. MCMVkoji izražava NKG2D ligand RAE-1γdrastično je atenuiran in vivoine kolonizira žlijezde slinovnice. Smanjen rastRAE-1γMCMV-a rezultira bržim nestajanjem virusne DNK iz krvi i smanjenom količinom latentnog virusnog genoma u tkivima odraslih, imunokompetentnih miševa i novookoćenih miševa s nedozrelim imunološkim sustavom. Infekcija ovim virusomje uspješno kontrolirana i u imunokompromitiranog domaćina kao što su miševa kojima nedostaje receptor za tip I interferone i u miševa imunokompromitiranih γ-zračenjem. Stanični i humoralni imunološki odgovor potaknut infekcijom RAE-1γMCMV-om usporediv je s onim nakon infekcije WT MCMV-om i štiti domaćina od letalne CMV infekcije. RAE-1γMCMV uspostavlja latencijus mogućnošćureaktivacije virusa u uvjetima imunosupresije. Usprkos snažnog selekcijskog tlaka imunološkog sustavaRAE-1γizražen kao transgen u RAE-1γMCMV genomu ne podliježe mutacijama.Imunizacija mišica RAE-1γMCMV-om štiti njihovumladunčadod CMV bolesti posredovano transplacentarno prenesenim virus-specifičnim protutijelima. IIZaključak: Receptor NKG2D igra važnu ulogu u uspostavi i održavanjulatentne CMV infekcije, te poticanju virus-specifičnog imunološkog odgovora. RekombinantanCMV konstruiran tako da izražava NKG2D ligand RAE-1γ je izvrstan kandidatza sigurnu i učinkovitu CMV vakcinuili vektor za izražaj antigena drugih patogena.Objectives:Of the study are to clarify the role of receptor NKG2D during latent cytomegalovirus (CMV) infection and in the process of priming and maintenance of virus-specific immune response. Materials and methods:Mice were infected with recombinant MCMVs lacking one of the NKG2D imunoevasion genes (Δm138 MCMV, Δm145MCMV and Δm152MCMV), MCMV expressingNKG2D ligand RAE-1γ(RAE-1γMCMV) or wild type MCMV (WT MCMV). Viral titers were determined by virus titration and viral DNA load by quantitative PCR. Kinetics and phenotype of virus-specific lymphocytes were tested by FACS analysis. Results: Despite early attenuation, recombinant MCMVs lacking any of the NKG2D immunovasion genes show late recoveryof infectious virus in salivary glands. Latent virus DNA load as well as kinetics and phenotype of virus-specific immune response after infection withMCMV deletion mutants and WT MCMV are comparable. RAE-1γMCMV is strongly attenuated in vivoand failsto establish persistentinfection in salivary glands. Strong attenuation of RAE-1γMCMV results in faster clearance of virus DNA from blood and significantly lower latent virus DNA load in tissues in adult, immunocompetent mice and in the newborn mice with immature immune system. Despite tight innate immune control RAE-1γMCMV infection elicits strong and enduring antiviral immune response that confersprotection against lethal MCMV infection. Strong attenuation does not prevent RAE-1γMCMV from establishing latency and reactivating upon immunosuppression. Infection with RAE-1γMCMV presentsa low risk for disease even in severely immunodeficient host such as mice lacking receptor for type I interferons and mice immunocompromised by γ-irradiation. In spite of the strong selective pressure by the immune system RAE-1γ remains intact during latent RAE-1γMCMV infection. Maternal RAE-1γMCMV immunization protects neonatal mice from MCMV infection upon placental transfer of antiviral antibodies. IVConclusions: Receptor NKG2D plays a major role during latent CMV infection and in the process of priming and maintenanceof virus-specific immune response. Recombinant CMV designedto expressNKG2D ligand is anexcellent candidate for a safe and immunogenicCMV vaccine or CMV-based vaccine vector