Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages carry distinct spike mutations and represent an antigenic shift resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters elicit plasma neutralizing activity against Omicron BA.1, BA.2, BA.2.12.1 and BA.4/5 and that breakthrough infections, but not vaccination-only, induce neutralizing activity in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1, BA.2, and BA.4/5 receptor-binding domains whereas Omicron primary infections elicit B cells of narrow specificity up to 6 months post infection. Although most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant neutralizing antibody, that is a strong candidate for clinical development.

Visceral leishmaniasis is a multisystemic zoonotic disease that can manifest with several symptoms, including neurological disorders. To investigate the pathogenesis of brain alterations occurring during visceral leishmaniasis infection, the expression of the cytokines IL-1β, IL-6, IL-10, IL-12p40, IFN-γ, TGF-β and TNF-α and their correlations with peripheral parasite load were evaluated in the brains of dogs naturally infected with Leishmania infantum. IL-1β, IFN-γ and TNF-α were noticeably up-regulated, and IL-10, TGF-β and IL-12p40 were down-regulated in the brains of infected dogs. Expression levels did not correlate with parasite load suggestive that the brain alterations are due to the host's immune response regardless of the phase of the disease. These data indicate the presence of a pro-inflammatory status in the nervous milieu of dogs with visceral leishmaniasis especially because IL-1β and TNF-α are considered key factors for the initiation, maintenance and persistence of inflammation.

In dogs, there is an association of chronic visceral leishmaniasis with neurological symptoms, and very few publications have investigated whether these neurological manifestations correlate with specific alterations in brain. A total of 42 mixed-breed adult dogs were selected from the Veterinary Hospital of UNESP-Araçatuba and the Control Zoonosis Center in Araçatuba, São Paulo State, Brazil, which is an endemic area for visceral leishmaniasis. Animals presenting positive ELISA and/or positive parasitological diagnosis of Leishmania were enrolled in the group of infected dogs (n=32). Animals with negative ELISA results and parasitological tests for Leishmania, including a negative immunofluorescence test for toxoplasmosis and neosporosis, were included as the control group (n=10). Brain samples were collected, stored in 10% buffered formalin and subjected to routine histological procedures, following by staining with haematoxylin-eosin (HE) and immunohistochemical examination for T and B lymphocytes and phagocytic cells. Cerebrospinal fluid was collected to determine the anti-Leishmania antibody titers. Histological examination of HE stains demonstrated intense inflammatory infiltrate, primarily in the choroid plexus, which was composed of mononuclear cells with no detectable parasites. Immunohistochemistry revealed that CD3(+) T lymphocytes were the major components of the inflammatory infiltrate at the choroid plexus and in the brain. Infected dogs had more CD3(+) T cells than uninfected animals (P=0.0002). Cerebrospinal fluid from infected dogs contained high titers of anti-Leishmania antibodies in comparison with control animals (P<0.0001), which suggests a compromise of the blood-cerebrospinal fluid barrier. Leukocyte entry into the brain suggests the participation of these cells in the pathogenesis of neurological disorders during the advanced stages of leishmaniasis and confirms that the choroid plexus is an important structure for T cell influx.

Visceral leishmaniasis is a multisystemic zoonotic disease that can manifest with several symptoms, including neurological disorders. Because glial cells are extensively associated with the immune response within the brain, we evaluated the morphology of astrocytes and microglia of dogs naturally infected with Leishmania chagasi. We used immunohistochemical and lectin-histochemical techniques for morphological analyses and we also examined the glial correlation with lymphocyte infiltration of the brain and with the presence of anti-Leishmania antibodies within the cerebrospinal fluid of the dogs. Although we did not detect a shared morphological pattern in the astrocytes or microglia in the brain tissue, these cells were more intensely labelled in infected dogs than in the control group. The density of microglia was increased in the ependymal/subependymal area, thus demonstrating a strong correlation with the presence of T lymphocytes and with cerebrospinal fluid antibody titres. Thus, our results indicate a pro-inflammatory state in the brains of dogs naturally infected with L. chagasi and strongly suggest that microglia and astrocytes are involved in the pathogenesis of the neurological disorders of visceral leishmaniasis in dogs.

BackgroundRecent studies have demonstrated numerous biological properties of mesenchymal stem cells and their potential application in treating complex diseases or injuries to tissues that have difficulty regenerating, such as those affecting the central and peripheral nervous system. Thus, therapies that use mesenchymal stem cells are promising because of their high capacity for self-regeneration, their low immunogenicity, and their paracrine, anti-inflammatory, immunomodulatory, anti-apoptotic and neuroprotective effects. In this context, the purpose of this study was to evaluate the feasibility and safety of intrathecal transplantation of bone marrow-derived mesenchymal stem cells in horses, for future application in the treatment of neurological diseases.ResultsDuring the neurological evaluations, no clinical signs were observed that were related to brain and/or spinal cord injury of the animals from the control group or the treated group. The hematological and cerebrospinal fluid results from day 1 and day 6 showed no significant differences (P > 0.05) between the treated group and the control group. Additionally, analysis of the expression of matrix metalloproteinase (MMP) -2 and −9 in the cerebrospinal fluid revealed only the presence of pro-MMP-2 (latent), with no significant difference (P > 0.05) between the studied groups.ConclusionsThe results of the present study support the hypothesis of the feasibility and safety of intrathecal transplantation of autologous bone marrow-derived mesenchymal stem cells, indicating that it is a promising pathway for cell delivery for the treatment of neurological disorders in horses.

Inflammation causes increases in the level of matrix metalloproteinases (MMPs), which, in central nervous system (CNS), are associated with neuroinflammation and disruption of blood-brain barrier. Analysis of cerebrospinal fluid (CSF) is pivotal for detecting diseases in CNS and, although a specific diagnosis may not be achieved, this analysis is helpful to confirm the diagnosis or to rule out relevant differential diagnoses. This study examined the levels of MMP-2 and MMP-9 in the CSF of dogs using gelatin zymography to verify possible alterations in these enzymes during natural systemic infection with Leishmania chagasi. Latent and active forms of MMP-2 were detected in some dogs of both groups, with high levels in the control group. In contrast, latent and active forms of MMP-9 were detected only in some animals with leishmaniasis. These results clearly demonstrate that MMP-9 is elevated in CSF of dogs with visceral leishmaniasis (VL). Although these results are preliminary, they suggest that MMP-9 might play a role in disruption of blood-brain barrier and/or blood-CSF barrier. While the presence of MMPs in CSF is not a condition exclusive to VL, their presence and persistence in CSF supports the hypothesis of an inflammatory state within CNS of dogs with VL.

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