scholarly journals CD45+, CD68+ and E-cadherin+ Expressions in Skin Dogs Naturally Infected by Leishmania infantum

2017 ◽  
Vol 45 (1) ◽  
pp. 7
Author(s):  
Társsila Mara Vieira Ferreira ◽  
Tiago Cunha Ferreira ◽  
Fernanda Maria Aragão Ximenes Porto ◽  
Conceição Da Silva Martins ◽  
Berlamino Eugênio Lopes Neto ◽  
...  
Keyword(s):  
Leishmania Infantum ◽  
Mononuclear Cells ◽  
Plasma Cells ◽  
Clinical Signs ◽  
Clinical Manifestations ◽  
Canine Leishmaniasis ◽  
Control Group ◽  
Asymptomatic Group ◽  
G Ratio ◽  
E Cadherin

Background: In canine leishmaniasis (CanL), infection occurs through phlebotomine vectors that inoculate the protozoan Leishmania infantum into the skin that infected macrophages and activated dendritic cells (CD). Dogs with CanL present variable clinical manifestations, being common the presence of cutaneous lesions. The aim of this study was to evaluate the expression of CD45+, CD68+ and E-cadherin+  associating the skin sentinels cells and to compare the clinical-dermatological manifestations in the skin of dogs naturally infected by L. infantum.Materials, Methods & Results: Dogs infected (n = 22) by L. infantum were divided into asymptomatic group (AD, n = 9), and symptomatic group (SD, n = 13), according criteria based on the presence or absence of skin changes. Dogs non-infected (CD, n = 5) were included as control group. Samples of skin biopsies collected from scapular region were processed by routine histology and labeled by immunohistochemistry with monoclonal antibodies against CD45+, CD68+ and E-cadherin+, and were described as none, mild, moderate and intense. SD presented keratoconjunctivitis, onychogryphose, lichenification, depigmentation, alopecia, hypotrichosis, erythematous dermatitis, exfoliative dermatitis, ulcerative dermatitis and crusted dermatitis, and the frequency these alterations was expressed as percentage. The results of hematological and biochemical parameters were analyzed by Kruskal-Wallis test followed by the Dunn’s test and expressed as mean ± standard deviation, with values P < 0.05. Leukocytosis (not significant), red blood cells, hematocrit and hemoglobin (P < 0.05), total protein serum (P < 0.05), globulins (P < 0.05), albumin and A/G ratio (P < 0.01) were altered in SD in relation to CD. Cutaneous cellular infiltration, composed by macrophages, plasma cells, lymphocytes and neutrophils, was observed in CD. There was an increase of expression of the markers in SD when compared to the other groups, as moderate CD68+ expression and L. infantum, and intense CD45+ and E-cadherin+ expressions.Discussion: Cutaneous involvement is very important in CanL, as it corresponds to where is the first interaction between the parasite and the immune system. Dermatological clinical signs, leukocytosis, anemia, globulins levels have been reported for dogs naturally infected by L. infantum. Inflammatory infiltrate was distributed at superficial and deep dermis, which was composed by mononuclear cells as macrophages, plasma cells, lymphocytes and neutrophils. To characterize the immune sentinels cells in the skin it was evaluated CD45+, CD68+ and E-cadherin+ expressions. In syntomatic dogs, our results revelead an increase of expression of these markers. CD45+ is one of the most abundant molecules expressed on the white blood cell surface in various mammals, while CD68+ is a myelomonocytic marker that seems to be retained during monocyte differentiation. In the skin, increased numbers of CD68+ are related to dendritic epidermal cells, which can be expressed as CD45+/CD1a-/HLA-DR+. DCs of the skin, particularly epidermal Langerhans cells (LCs), form networks anchored to neighboring keratinocytes via E-cadherin. Thus, CD45+, CD68+ and E-cadherin+ expressions may be related to activation of skin sentinels cells in dogs naturally infected by L. infantum. Our results indicated that CanL modify the CD45+, CD68+ and E-cadherin+ expressions, which characterize the immune sentinels cells activation that promove the recruitment the cellular infiltrate, which was composed by macrophages, plasma cells, lymphocytes and neutrophils. Thus, these informations may contribute to the follow-up of CanL progression in skin.

scholarly journals Relationship between clinical and pathological signs and severity of canine leishmaniasis

2013 ◽  
Vol 22 (3) ◽  
pp. 373-378 ◽  
Author(s):  
Raul Rio Ribeiro ◽  
Sydnei Magno da Silva ◽  
Gustavo de Oliveira Fulgêncio ◽  
Marilene Suzan Marques Michalick ◽  
Frédéric Jean Georges Frézard
Keyword(s):  
Clinical Signs ◽  
Reference Interval ◽  
Canine Leishmaniasis ◽  
Control Group ◽  
Asymptomatic Group ◽  
Mean Values ◽  
Clinical Forms ◽  
The Mean ◽  
Clinical Conditions ◽  
G Ratio

Canine visceral leishmaniasis (CVL) is a zoonotic disease that presents variable clinical and laboratory aspects. The aims of this study were to identify the main biochemical/hematological status of dogs naturally infected with Leishmania (Leishmania) infantum and to associate theses parameters with clinical forms of CVL. Blood samples were analyzed from 51 dogs, 15 uninfected (control group) and 36 infected, which were classified clinically in three groups: asymptomatic (n=12), oligosymptomatic (n=12) and symptomatic (n=12). All the infected dogs showed lower albumin/globulin ratios (A-G ratio) than the limit of reference. The mean values of total protein, urea, α-globulin 2, globulin and A-G ratio of infected dogs were outside the reference interval and differed significantly from those of the controls. Anemia was detected only in groups that showed clinical signs of the disease, and a statistical analysis indicated a significantly higher frequency of lower eritrogram in these groups than in the asymptomatic group. In addition, a significant association was observed between anemia and the presence of the symptoms, with dogs displaying higher erythrogram values showing better clinical conditions. These results provide additional evidence that the clinical forms of CVL may reflect on the erythrogram status.

scholarly journals Canine Leishmaniasis in Morocco: A Descriptive Prospective Clinical Study

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Houda Idrissi ◽  
Maryam Hakkour ◽  
Luc Duchateau ◽  
Renato Zanatta ◽  
Malika Kachani ◽  
...  
Keyword(s):  
Urban Areas ◽  
Leishmania Infantum ◽  
Clinical Signs ◽  
Clinical Manifestations ◽  
Outdoor Environment ◽  
Exercise Intolerance ◽  
Canine Leishmaniasis ◽  
Effective Control ◽  
Prospective Clinical Study ◽  
Free Access

Canine leishmaniasis (CanL) is a zoonotic vector-borne disease that is endemic in the Mediterranean Basin including Morocco. Dogs play a major epidemiological role in this zoonosis as reservoir hosts. This study investigated the clinical manifestations of CanL in dogs naturally infected with Leishmania infantum. A total of 96 dogs presented to the Small Animal Clinic of the Hassan II Agronomy and Veterinary Institute (IAV Hassan II) of Rabat, Morocco, and were tested by RT-PCR and/or serology. Among them, 32 (33.3%) were positive to Leishmania infantum infection. The majority of the positive dogs (93.7%) came from urban areas. Most of them were male (62.5%) and purebreds (65.6%), were aged between 3 and 7 years (71.8%), and had outside activities (guarding, hunting, livestock guarding, and service activities) (71.8%) and all of them were living exclusively outdoor or had free access to the outdoor environment. Lymphadenomegaly (81.2%), dermatological disorders (65.6%) (mostly exfoliative dermatitis), weight loss (59.3%), exercise intolerance (56.2%), anorexia (28.1%), hyporexia (15.6%), and ocular lesions (28.1%) were the most frequent clinical signs and complaints recorded. Anemia and hyperproteinemia due to hyperglobulinemia were observed in 68.7% and 72.7% of the cases, respectively. These results suggest that CanL leads to various nonspecific clinical signs as described previously, making the diagnosis challenging. Since CanL is endemic in Morocco, it should be recommended to systematically test dogs displaying clinical signs compatible with this disease and to regularly screen asymptomatic at-risk dogs. It is also crucial to educate dog owners about the zoonotic aspect of the disease and to encourage intersectorial collaboration following the “One Health” concept, in order to contribute to a more effective control/prevention of human and canine leishmaniasis.

scholarly journals Bullous Pemphigoid in a Dog

2021 ◽  
Vol 49 ◽  
Author(s):  
Suélen Dalegrave ◽  
Denner Francisco Tomadon Fiorin ◽  
Eduarda Gabriela Mansour ◽  
Monica Regina De Matos ◽  
Renato Herdina Erdmann ◽  
...  
Keyword(s):  
Bullous Pemphigoid ◽  
Plasma Cells ◽  
Histopathological Examination ◽  
Clinical Signs ◽  
Clinical Manifestations ◽  
Punch Biopsy ◽  
Mucous Membrane Pemphigoid ◽  
Histopathological Analysis ◽  
Biopsy Material ◽  
Clinicopathological Findings

Background: In dogs, bullous pemphigoid (BP) is a subepithelial autoimmune disease, a rare dermatopathy in the clinical routine. BP is characterized by formation of vesicles and subepidermal blisters that result from dissolution of the dermal-epithelial junction. Clinical signs of BP usually include severe dermatological alterations with a variable prognosis. The aim of this work is to report a case of BP in a dog to contribute information for diagnosis, and to present clinical and pathological aspects that emerge during development of BP.Case: An adult male mongrel dog exhibited hyperemic, exudative, crusty lesions on the lip commissure and periocular areas. Results from laboratory tests were normal. Results from parasitological and mycological tests on skin scrapings were negative. Imprint cytology of the crusts revealed presence of gram-positive cocci bacteria. In the histopathological analysis of punch biopsy material, the epidermis was detached from the dermis, leading to formation of vesicles. There were inflammatory infiltrates containing neutrophils, eosinophils, and high amounts of fibrin, and areas of multifocal orthokeratotic hyperkeratosis. Multifocal infiltrates containing lymphocytes, histiocytes, and plasma cells were observed on the superficial portions of the dermis, which indicated a diagnosis of BP. After the definitive clinical diagnosis, the animal was treated with enrofloxacin (Baytril Flavour®; 5 mg/kg once a day for 10 days), and prednisolone (Prediderm®; 2 mg/kg once a day until further instructions). On the follow-up visit, 15 days later, the clinical picture had improved, and the lesions had decreased. Continuity of the treatment was prescribed, along with a gradual decrease in the corticoid dose. The dose of prednisolone was initially reduced to 1 mg/kg once a day, and later to 0.5 mg/kg until improvement of the clinical status of the patient. Remission of the lesions was observed 13 weeks later.Discussion: The diagnosis of BP was established after identification of the clinical cutaneous lesions and observation of microscopic findings on punch biopsy material obtained from the ocular and lip regions. BP does not exhibit breed or sex predisposition, and affects adult dogs. The clinical signs of BP are characteristic of autoimmune diseases that affect the dermoepidermal junction, and consist of erythematous, ulcerated, crusty, and painful lesions on the nose, dorsal area of the muzzle, and periorbital region. However, these lesions must be differentiated, by histological analysis, from several other conditions with a similar clinical presentation. Diseases that must be considered in the differential diagnosis comprise other variants of the pemphigus complex, lupus erythematosus, drug eruption, erythema multiforme, toxic epidermal necrolysis, epitheliotropic lymphoma, inherited bullous epidermolysis, mucous membrane pemphigoid, and lymphoreticular neoplasia. The clinicopathological findings indicated that the lesions were compatible with BP. The occurrence of necrotic and erythematous lesions is due to production of antibodies accompanied by a strong response of neutrophils, which results in loss of cell adhesion and epidermal necrosis. The presence of detachment of the epidermis from the dermis, inflammation in the superficial portion of the dermis, and infiltrates containing lymphocytes, histiocytes and plasma cells observed at the histopathological examination indicated the occurrence of BP. The skin histopathological examination warranted establishment of a diagnosis and therapeutic success. The lack of recurrence of clinical manifestations 43 weeks after the end of the glucocorticoid treatment demonstrated that the therapeutic approach and the cooperation of the owner are essential for success of the treatment.

scholarly journals GENETIC ASPECTS OF PREGNANCY MISCARRIAGE

2019 ◽  
pp. 71-76
Author(s):  
K. M. Lisova ◽  
I. V. Kalinovska ◽  
O. M. Yuzko
Keyword(s):  
Pregnant Women ◽  
Molecular Genetic ◽  
Clinical Signs ◽  
Clinical Manifestations ◽  
Control Group ◽  
Molecular Genetic Study ◽  
Immunological Parameters ◽  
Fetoplacental Complex ◽  
Maternal Genotype ◽  
A1166c Polymorphism

Pregnancy miscarriage is a consequence of many factors. The aim of the study was to analyze the effect of miscarriage gene on embryometric, ultrasound, hormonal, immunological parameters in pregnant women, and to evaluate its prognostic value. The main group includes 31 pregnant women who had clinical signs of miscarriage in current or previous pregnancy. The control group consists of 32 healthy pregnant women whose clinical-paraclinical parameters served as a control to compare the data of the pregnancy survey of the main surveillance group. A general clinical examination and a special obstetrical examination (complaints, anamnesis, general medical examination, obstetric examination), biochemical studies (determination of hormones of the fetoplacental complex in blood serum of pregnant women), ultrasound, immunological studies, histological studies of the placenta, molecular genetic study A1166C polymorphism of the AGTR1 gene were made. In the course of the research, the genetic determinism of miscarriage was discovered. The polymorphism of the A1166C of the AGTR1 gene was considered as a prognostic marker of miscarriage in early gestational term and preeclampsia in the second half of pregnancy. A reliable marker of abortion was the maternal genotype 1166AC for the genome AGTR1. The risk of occurrence of clinical manifestations of abortion increased five times. At simultaneous influence of all prognostic factors the risk of abortion increased 6,25 times. Detection of genetic markers of pregnancy miscarriage will allow early correction of this pathology and prevent perinatal loss.

↵​Haemato-biochemical and Therapeutic Studies on Ovine Babesiosis in Kashmir

2021 ◽  
Author(s):  
A.U. Haq ◽  
N.A. Tufani ◽  
H.U. Malik ◽  
T.A. Najar
Keyword(s):  
Clinical Signs ◽  
Clinical Manifestations ◽  
Control Group ◽  
Diminazene Aceturate ◽  
Group I ◽  
Blood Smears ◽  
Imidocarb Dipropionate ◽  
Calcium Phosphorus ◽  
Healthy Control ◽  
Therapeutic Study

Background: The clinical study was designed to evaluate the haemato-biochemical changes in sheep affected with babesiosis and therapeutic regimes of various drugs used against babesiosis. Methods: A total of 24 clinically affected sheep with 6 animals in each group were selected for the haemato-biochemical and therapeutic study. The diagnosis was based on clinical manifestations, microscopic examination of blood smears and molecular confirmation of Babesia by PCR technique. For therapeutic study Group I, II, III and IV were treated with imidocarb dipropionate, imidocarb dipropionate+oxytetracycline, diminazene aceturate and diminazene aceturate+oxytetracycline, respectively. Result: The clinical signs recorded were high fever, pale mucous membranes, presence of ticks, inappetence, coffee-coloured urine and diarrhoea. The vectors identified were Haemaphysalis ticks. Hb, PCV, TEC, total protein, albumin, calcium, phosphorus and blood glucose were significantly (P less than 0.05) lower in the diseased group as compared to healthy animals while TLC, globulin and iron levels were significantly (P less than 0.05) higher compared to the healthy control group. The study revealed that the combination of imidocarb dipropionate and oxytetracycline was highly effective for ovine babesiosis.

The Effect of Acupuncture on Proinflammatory Cytokine Production in Patients with Chronic Headache: A Preliminary Report

2003 ◽  
Vol 31 (06) ◽  
pp. 945-954 ◽  
Author(s):  
Hyun-Ja Jeong ◽  
Seung-Heon Hong ◽  
Yong-Che Nam ◽  
Hee-Sook Yang ◽  
Yeoung-Su Lyu ◽  
...  
Keyword(s):  
Chronic Headache ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Acupuncture Treatment ◽  
Clinical Signs ◽  
Inhibitory Effect ◽  
Acute Stage ◽  
Control Group ◽  
Peripheral Blood Mononuclear ◽  
Tnf Α

Acupuncture has been widely used as a treatment for various conditions like headache and stroke, especially in Asian countries such as Korea and China. But few scientific investigations have been carried out. The aim of the present study is to investigate the effect of acupuncture on the production of inflammatory cytokines in patients with chronic headache (CH). Patients with CH were treated with acupuncture during the acute stage. Clinical signs of CH disappeared markedly after three months of treatment with acupuncture. Peripheral blood mononuclear cells obtained from a normal group and those from the patients with CH, before and after treatment with acupuncture, were cultured for 24 hours in the presence or absence of lipopolysaccharide (LPS). The amount of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) in LPS culture supernatant was significantly increased in the patients with CH compared to the healthy control group (p < 0.05). But those cytokines came down toward the levels of the healthy group (p < 0.05) after treatment with acupuncture, although the levels still remained elevated. Plasma cytokine levels were analyzed to evaluate any change due to acupuncture treatment. There was little difference in the levels of IL-1β or IL-6 due to the treatment with acupuncture in the patients with CH, but significantly reduced plasma levels of TNF-α were observed. These data suggest that acupuncture treatment has an inhibitory effect on pro-inflammatory cytokine production in patients with CH.

scholarly journals Seroprevalence and risk factors associated with Leishmania infantum in dogs in Sardinia (Italy), an endemic island for leishmaniasis

2020 ◽  
Author(s):  
Claudia Tamponi ◽  
Fabio Scarpa ◽  
Silvia Carta ◽  
Stephane Knoll ◽  
Daria Sanna ◽  
...  
Keyword(s):  
Risk Factors ◽  
Clinical Signs ◽  
Clinical Manifestations ◽  
General Information ◽  
Canine Leishmaniasis ◽  
Igg Antibodies ◽  
Epidemiological Surveys ◽  
Chi Squared ◽  
Vector Borne ◽  
First Time

AbstractLeishmaniasis is a widespread, vector-borne parasitosis causing clinical manifestations in animals and in humans. In dogs, Canine Leishmaniasis has been reported in as much as 50 countries and the Mediterranean basin is known to be one of the most affected zones. Within these areas, the Island of Sardinia (Italy) has long been considered endemic for leishmaniasis and the presence of two arthropod vectors has recently been reported there. Nevertheless, to date, no epidemiological surveys regarding CanL have been carried out on the island. Hence, for the first time, the seroprevalence and the risk factors were investigated. Blood samples, as well as clinical and general information from 1.147 dogs, were collected and analyzed. Dogs consisted of two distinct populations, namely “owned dogs” and “kennel dogs.” Anti-Leishmania IgG antibodies were detected using IFAT and samples were scored as positive at a cut-off dilution of 1:80. Data was analyzed using a Chi-squared test and bivariate and multivariate analyses were performed. Overall, 15.4% of dogs were found to be infected with CanL while only 44.1% of these animals exhibited clinical signs. Owned dogs (27.2%) were found to be infected more often than kennel dogs (10.6%); male dogs were found to be more frequently infected than female dogs and the number of infected animals increases with age. The present survey confirmed the endemic nature of leishmaniasis in Sardinia with a similar seroprevalence as mainland Italy. The results obtained serve as validation for the hypothesis that, in endemic areas, clinical CanL representations constitute only a fraction of the leishmaniasis cases.

scholarly journals Seroepidemiology of Leishmania infantum in dogs in the city of Porto Alegre, Rio Grande do Sul, Brazil

2016 ◽  
Vol 37 (6) ◽  
pp. 4077 ◽  
Author(s):  
Mariana Caetano Teixeira ◽  
Neusa Saltiel Stobbe ◽  
Verônica Schmidt ◽  
Valéria Marçal Felix de Lima ◽  
Ana Luisa Tartarotti ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Leishmania Infantum ◽  
Clinical Manifestations ◽  
Rio Grande ◽  
The State ◽  
Canine Leishmaniasis ◽  
Insect Vector ◽  
Rio Grande Do Sul ◽  
Porto Alegre ◽  
The City

Leishmaniosis are zoonoses that present several clinical manifestations in humans and have dogs as their main reservoir in the urban environment. Visceral leishmaniasis (VL) is the most severe form of the parasitosis and has been increasing in Brazil, despite the actions of public health agencies. Until 2002, the State of Rio Grande do Sul (RS) was considered free of human and canine leishmaniasis. The first human case of cutaneous leishmaniasis in RS was recorded in 2003. In 2009, the first autochthonous cases of human VL and canine visceral leishmaniasis (CVL) were confirmed in São Borja, RS, and the occurrence of the insect vector was recorded for the first time in the state. In 2010, the first confirmed case of CVL was reported and seropositive dogs were identified in the city of Porto Alegre, RS. Given the importance of this zoonosis and the difficulties of a reliable diagnosis in dogs, this study aimed to identify epidemiological aspects of CVL in dogs in an area of Porto Alegre where cases of the disease have been reported. A total of 300 blood samples were collected from dogs in this area, which were then tested by the methods of RT-DPP® and ELISA for diagnosis of Leishmania infantum. An epidemiological questionnaire was completed by dog owners, containing aspects related to care of the animals, characteristics of their environment, and their living conditions. We observed that 83% (250/300) of the studied dogs were of mixed breed, 58% (175/300) were female, 78% (238/300) slept outdoors, and 61% (183/300) shared their living quarters with other species. Clinically, we observed that 90% (270/300) of the animals were infested by ectoparasites, 70% (210/300) had dermatopathies, 24% (72/300) presented weight loss and anorexia, and 22% (65/300) had ocular disorders. The results of the two serological tests were 100% concordant for the three seropositive samples (1%), and the remaining 297 (99%) were negative for both tests. We conclude that despite the low prevalence of L. infantum seropositive dogs, conditions in the region are favorable for CVL transmission, creating a risk of VL for the human population in the city of Porto Alegre.

scholarly journals Toward Diagnosing Leishmania infantum Infection in Asymptomatic Dogs in an Area Where Leishmaniasis Is Endemic

2009 ◽  
Vol 16 (3) ◽  
pp. 337-343 ◽  
Author(s):  
D. Otranto ◽  
P. Paradies ◽  
D. de Caprariis ◽  
D. Stanneck ◽  
G. Testini ◽  
...  
Keyword(s):  
Leishmania Infantum ◽  
Clinical Signs ◽  
Antibody Test ◽  
Diagnostic Methods ◽  
Canine Leishmaniasis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Canine Monocytic Ehrlichiosis ◽  
Immunofluorescence Antibody Test ◽  
Immunofluorescence Antibody

ABSTRACT The most frequently used diagnostic methods were compared in a longitudinal survey with Leishmania infantum-infected asymptomatic dogs from an area of Italy where leishmaniasis is endemic. In February and March 2005, 845 asymptomatic dogs were tested by an immunofluorescence antibody test (IFAT), a dipstick assay (DS), and an enzyme-linked immunosorbent assay (ELISA) for L. infantum and by IFAT for Ehrlichia canis. Dogs seronegative for L. infantum were further parasitologically evaluated by microscopic examination of lymph node tissues and PCR of skin samples. A total of 204 animals both serologically and parasitologically negative for L. infantum at the first sampling were enrolled in the trial and were further examined for canine leishmaniasis (CanL) and canine monocytic ehrlichiosis in November 2005 (i.e., the end of the first sandfly season) and March 2006 and 2007 (1- and 2-year follow-ups, respectively). At the initial screening, the overall rates of L. infantum seroprevalence were 9.5% by IFAT, 17.1% by ELISA, and 9.8% by DS and the overall rate of E. canis seroprevalence was 15%. The rates of concordance between the results of IFAT and DS were almost equal, whereas the rate of concordance between the results of IFAT and DS and those of the ELISA was lower. The results of the annual incidence of Leishmania infection were variable, depending on the test employed, with the highest values registered for PCR (i.e., 5.7% and 11.4% at the 1- and 2-year follow-ups, respectively), followed by ELISA, IFAT, and DS. Over the 2 years of observation, 55 animals (i.e., 26.9%) became positive for L. infantum by one or more diagnostic tests at different follow-up times, with 12.7% showing clinical signs related to CanL, while the remaining 87.3% were asymptomatic. A diagnostic scheme for assessment of the L. infantum infection status in asymptomatic dogs is suggested.

scholarly journals Sequential Immunization with Universal Live Attenuated Influenza Vaccine Candidates Protects Ferrets against a High-Dose Heterologous Virus Challenge

2018 ◽  
Author(s):  
Irina Isakova-Sivak ◽  
Victoria Matyushenko ◽  
Tatiana Kotomina ◽  
Irina Kiseleva ◽  
Elena Krutikova ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Clinical Signs ◽  
Clinical Manifestations ◽  
Cd8 T Cell ◽  
Influenza Viruses ◽  
Influenza Vaccines ◽  
Control Group ◽  
High Dose ◽  
T Cell Immune Responses

The development of universal influenza vaccines, i.e. vaccines that can provide broad protection against seasonal and potentially pandemic influenza viruses, has been a priority for more than 20 years. Several approaches have been proposed that redirect the adaptive immune responses from immunodominant hypervariable regions to low-immunogenic but highly conserved regions of viral proteins. Here we induced broadly reactive anti-hemagglutinin (HA) stalk antibody by sequential immunizations with live attenuated influenza vaccines (LAIVs) expressing chimeric HA (cHA). These vaccines contained the HA stalk domain from H1N1pdm09 virus but antigenically unrelated globular head domains from avian influenza viruses H5N1, H8N4 and H9N2. In addition, the source of the viral nucleoprotein (NP) of the LAIV strains was changed from A/Leningrad/17 master donor virus (MDV) to wild-type (WT) H1N1pdm09 virus, in order to induce CD8 T-cell immune responses more relevant to current infections. To avoid any difference in protective effect of the various anti-neuraminidase (NA) antibodies, all LAIVs were engineered to contain the NA gene of Len/17 MDV. Na&iuml;ve ferrets were immunized with three doses of (i) classical LAIVs containing non-chimeric HA and NP from MDV (LAIVs (NP-MDV)); (ii) cHA-based LAIVs containing NP from MDV (cHA LAIVs (NP-MDV)); and (iii) cHA-based LAIVs containing NP from H1N1pdm09 virus (cHA LAIVs (NP-WT)). A high-dose challenge with H1N1pdm09 virus induced significant pathology in the control, non-immunized ferrets, including high virus titers in respiratory tissues, clinical signs of disease and histopathological changes in nasal turbinates and lung tissues. All three vaccination regimens protected animals from clinical manifestations of disease: immunized ferrets did not lose weight or show clinical symptoms, and their fever was significantly lower than in the control group. Further analysis of virological and pathological data revealed the following hierarchy in the cross-protective efficacy of the vaccines: cHA LAIVs (NP-WT) &gt; cHA LAIVs (NP-MDV) &gt; LAIVs (NP-MDV). This ferret study showed that prototype universal LAIVs that combine the two approaches of inducing anti-HA stalk antibody and more relevant CD8 T-cell immune responses are highly promising candidates for further clinical development.

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