Infectious diseases may affect brain function and cause encephalopathy even when the pathogen does not directly infect the central nervous system, known as infectious disease-associated encephalopathy. The systemic inflammatory process may result in neuroinflammation, with glial cell activation and increased levels of cytokines, reduced neurotrophic factors, blood–brain barrier dysfunction, neurotransmitter metabolism imbalances, and neurotoxicity, and behavioral and cognitive impairments often occur in the late course. Even though infectious disease-associated encephalopathies may cause devastating neurologic and cognitive deficits, the concept of infectious disease-associated encephalopathies is still under-investigated; knowledge of the underlying mechanisms, which may be distinct from those of encephalopathies of non-infectious cause, is still limited. In this review, we focus on the pathophysiology of encephalopathies associated with peripheral (sepsis, malaria, influenza, and COVID-19), emerging therapeutic strategies, and the role of neuroinflammation. Graphic abstract

We present a method for the examination of antiidiotypic cellmediated reactivity during chronic human infections. Pooled and individual sera from patients with schistosomiasis. mansoni were purified on immunoaffinity columns of schistosomal egg antigens (SEA). The eluates contained anti-SEA antibodies, but not SEA. These antibody preparations, and their F(ab')2 fragments, stimulated dose-dependent proliferation of peripheral blood mononuclear cells (PBMN) and T lymphocytes from some, but not all active or former schistosomiasis mansoni patients, and could do so autologously. Stimulation required presentation by plasticadherent cells. The eluates did not stimulate PBMN from persons who had never had schistosomiasis. Affinity-purified anti-SEA antibodies from former patients (cured for >10 yr) did not stimulate PBMN from patients with active infections. Reabsorption on SEA columns removed stimulatory activity from the eluates. We propose that multiclonal, SEA-related idiotypes expressed by some anti-SEA antibodies stimulate proliferation of T lymphocytes that express antiidiotypic specificities.

Objectives: Survivors of sepsis are frequently left with significant cognitive and behavioral impairments. These complications derive from nonresolving inflammation that persists following hospital discharge. To date, no study has investigated the effects of mesenchymal stromal cell therapy on the blood-brain barrier, astrocyte activation, neuroinflammation, and cognitive and behavioral alterations in experimental sepsis. Design: Prospective, randomized, controlled experimental study. Setting: Government-affiliated research laboratory. Subjects: Male Swiss Webster mice (n = 309). Interventions: Sepsis was induced by cecal ligation and puncture; sham-operated animals were used as control. All animals received volume resuscitation (1 mL saline/mouse subcutaneously) and antibiotics (meropenem 10 mg/kg intraperitoneally at 6, 24, and 48 hours). Six hours after surgery, mice were treated with mesenchymal stromal cells IV (1 × 105 cells in 0.05 mL of saline/mouse) or saline (0.05 mL IV). Measurements and Main Results: At day 1, clinical score and plasma levels of inflammatory mediators were increased in cecal ligation and puncture mice. Mesenchymal stromal cells did not alter clinical score or survival rate, but reduced levels of systemic interleukin-1β, interleukin-6, and monocyte chemoattractant protein-1. At day 15, survivor mice completed a battery of cognitive and behavioral tasks. Cecal ligation and puncture mice exhibited spatial and aversive memory deficits and anxiety-like behavior. These effects may be related to increased blood-brain barrier permeability, with altered tight-junction messenger RNA expression, increased brain levels of inflammatory mediators, and astrogliosis (induced at day 3). Mesenchymal stromal cells mitigated these cognitive and behavioral alterations, as well as reduced blood-brain barrier dysfunction, astrocyte activation, and interleukin-1β, interleukin-6, tumor necrosis factor-α, and interleukin-10 levels in vivo. In cultured primary astrocytes stimulated with lipopolysaccharide, conditioned media from mesenchymal stromal cells reduced astrogliosis, interleukin-1β, and monocyte chemoattractant protein-1, suggesting a paracrine mechanism of action. Conclusions: In mice who survived experimental sepsis, mesenchymal stromal cell therapy protected blood-brain barrier integrity, reduced astrogliosis and neuroinflammation, as well as improved cognition and behavior.

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Brazilian army conscripts were vaccinated against American cutaneous leishmaniasis by using nonliving polyvalent promastigote Leish vaccine S or Leish vaccine 6 (vaccines with five or six Leishmania stocks) with or without Corynebacterium parvum. No statistically significant differences in lymphocyte stimulation indices were found between vaccinated groups with or without C. parvum, but lymphocyte stimulation indices of all vaccinees were significantly higher (P < 0.001) than those of the placebo group. A correlation of 90% was found between positive skin test results and positive lymphocyte stimulation indices. Eight major antigens with estimated molecular masses of 13.5, 25, 40, 63, 73, 85, 97, and 160 kilodaltons were recognized by Leish vaccine 5 sera. Our finding also demonstrated the predominance of immunoglobulin M antibody in sera of vaccinated subjects and that a component of Leish vaccine 5, gp63, was immunogenic in humans both at the T-cell level and at the antibody level. * Corresponding author. zil, revealed statistically significant differences in infection rates between vaccinated and nonvaccinated groups (22). A recent field trial conducted in the Amazon jungle, an area of high risk, revealed reductions of 67.3% in 1980 and 85.7% in 1983 in the incidence of the disease among vaccinees who had gone from a negative to a positive leishmania skin test (1). In this report, we present data about the correlation between skin test results and lymphocyte stimulation indices (LSIs). The effect of Corynebacterium parvum as an adjuvant in both vaccines is examined, and the immunogenicity of gp63, a component of the vaccine, is discussed. MATERIALS AND METHODS Leishmania stocks. The following Leishmania stocks were used in these studies: (i) L. mexicana (MHOM/BR/60/BH6); (ii) L. mexicana (MHOM/BR/71/BH49); (iii) L. mexicana complex (MHOM/BR/73/BH121) (these three stocks were isolated from patients with cutaneous leishmaniasis from Ceara, Goias, and Minas Gerais States, respectively, Brazil); (iv) L. amazonensis (IFLA/BR/67/PH8), isolated from a naturally infected sand fly caught in Para State, Brazil; (v) L. guyanensis (MHOM/BR/73/M1176); and (vi) L. braziliensis (MHOM/BR/73/M2903). These last two stocks were isolated from patients with cutaneous leishmaniasis from Para State, Brazil. Promastigotes of BH6, BH49, BH121, M2903, and PH8 were obtained by growing the first four stocks in acellular LIT medium (6) and by growing M1176 in T medium (8). Vaccines. Two vaccines were prepared as described previously (22). The Leishmania vaccine with five stocks (Leish vaccine 5) consisted of killed promastigotes from strains BH6, BH49, BH121, PH8, and M1176 at a concentration of 800 jig of protein per ml per stock. The Leishmania vaccine with six stocks (Leish vaccine 6) was prepared by the addition of 800 jig of protein per ml from promastigotes of L. braziliensis stock 2903 to Leish vaccine 5. Both vaccines were used with or without C. parvum as an adjuvant. Merthiolate at a final concentration of 1: 10,000 was added to...