The ongoing global pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and significantly impacts the world economy and daily life. Symptoms of COVID-19 range from asymptomatic to fever, dyspnoea, acute respiratory distress and multiple organ failure. Critical cases often occur in the elderly and patients with pre-existing conditions. By binding to the angiotensin-converting enzyme 2 receptor, SARS-CoV-2 can enter and replicate in the host cell, exerting a cytotoxic effect and causing local and systemic inflammation. Currently, there is no specific treatment for COVID-19, and immunotherapy has consistently attracted attention because of its essential role in boosting host immunity to the virus and reducing overwhelming inflammation. In this review, we summarise the immunopathogenic features of COVID-19 and highlight recent advances in immunotherapy to illuminate ideas for the development of new potential therapies.

One of the Leishmania species known to be non-infective to humans is Leishmania (Mundinia) enriettii whose vertebrate host is the guinea pig Cavia porcellus. It is a good model for cutaneous leishmaniasis, chemotherapeutic and molecular studies. In the last years, an increased interest has emerged concerning the L. (Mundinia) subgenus after the finding of Leishmania (M.) macropodum in Australia and with the description of other new/putative species such as L. (M.) martiniquensis and ‘L. (M.) siamensis’. This review focused on histopathology, glycoconjugates and innate immunity. The presence of Leishmania RNA virus and shedding of extracellular vesicles by the parasite were also evaluated.

CBA/T6 strain mice infected with Plasmodium berghei ANKA develop cerebral symptoms and die, with mononuclear cell attachment to the cerebral microvascular endothelium, petechial haemorrhages and breakdown of the blood–brain barrier, some 6–7 days post-inoculation. The effects of dietary restriction on this process were examined. Mice were fed ab libitum (Group 1) or their food was restricted to produce body weight loss of 1·0–2·0 % (Group 2), 2·5–3·5 % (Group 3), 4·0–6·5 % (Group 4) or 7·0–9·5 % (Group 5) relative to Group 1. Dietary restriction reduced deaths caused by cerebral malaria from 100% in Group 1 to 47% (Group 2), 43% (Group 3), 10% (Group 4) and 53% (Group 5). Restriction of food intake had no effect on (1) the progression of parasitaemia in infected mice (2) changes in haematocrit, spleen weight, total lymph node cell number or (3) peritoneal exudate cell number in either malaria-infected or uninfected mice. P. berghei ANKA infection did not significantly affect the proportion of lymph node leucocytes that were Thy-1+T cells or CD8+T cells, but did lead to significant increases in the CD4+ and B cell populations. Dietary restriction alone increased the lymph node CD4+cell population but did not affect the increase in B cells in malaria-infected mice. P. berghei ANKA infection and dietary restriction together did not lead to increased CD4+cell numbers in lymph node leucocytes. The in vitro proliferative response of isolated lymph node cells to concanavalin A or phorbol myristate acetate plus ionomycin was measured and found to be identical in all treatment groups. Plasma levels of tumour necrosis factor (TNF) increased from undetectable in uninfected mice or P. berghei ANKA-infected mice on days 1–6 post-inoculation to 21 ± 2 ng/ml on day 7 when cerebral symptoms were at their height and death was imminent. This increase in plasma TNF was substantially inhibited in those mice subjected to regimes of dietary restriction. There was a good correlation (r2 = 0·73) between plasma TNF level and percentage mortality in the 5 treatment groups. The results indicate that dietary status is an important factor in the outcome of murine cerebral malaria and perhaps, by extrapolation, in the human disease.

The pro-inflammatory cytokine tumour necrosis factor alpha (TNF-α) is associated with malaria virulence (disease severity) in both rodents and humans. We are interested in whether parasite genetic diversity influences TNF-mediated effects on malaria virulence. Here, primary infections with genetically distinct Plasmodium chabaudi chabaudi (P.c.c.) clones varied in the virulence and cytokine responses induced in female C57BL/6 mice. Even when parasitaemia was controlled for, a greater day 7 TNF-α response was induced by infection with more virulent P.c.c. clones. Since many functions of TNF-α are exerted through TNF receptor 1 (TNFR1), a TNFR-1 fusion protein (TNFR-Ig) was used to investigate whether TNFR1 blockade eliminated clone virulence differences. We found that TNFR-1 blockade ameliorated the weight loss but not the anaemia induced by malaria infection, regardless of P.c.c. clone. We show that distinct P.c.c. infections induced significantly different plasma interferon gamma (IFN-γ), interleukin 6 (IL-6) and interleukin 10 (IL-10) levels. Our results demonstrate that regardless of P.c.c. genotype, blocking TNFR1 signalling protected against weight loss, but had negligible effects on both anaemia and asexual parasite kinetics. Thus, during P.c.c. infection, TNF-α is a key mediator of weight loss, independent of parasite load and across parasite genotypes.

Immunopathology of Chagas' disease in Balb/c mice infected with 2 Trypanosoma cruzi clones, belonging to the T. cruzi I lineage and presenting different in vitro virulence (P/209 cl1>SO34 cl4) was compared. In the acute phase, evading mechanisms such as parasite-induced lymphocyte polyclonal activation and T cell immunosuppression were higher in mice infected with the clone giving a higher parasitaemia (P/209 cl1). A similar increase of non-specific isotypes was observed in both infections with IgG2a prevalence. Interestingly, CD8+ cell hypercellularity and lymphocyte immunosuppression were observed during the chronic phase (245 days post-infection) in mice infected by the most virulent clone. In the same way, the parasite-specific antibody response was more intense in P/209 cl1-infected mice over the acute phase. During the chronic phase this response remarkably dropped down in SO34 cl4-infected mice exclusively. Finally, P/209 cl1-infected mice presented a more severe inflammation and tissue damage in heart and quadriceps than SO34 cl4-infected mice. This comparative study showed differences between the two clones: a higher virulence in vivo being clearly associated with a greater ability to induce evasion mechanisms and severe tissue damage.

Infection of the cornea with herpes simplex virus (HSV) can result in a chronic disease called herpetic stromal keratitis (HSK). The disease represents one of the leading causes of infectious blindness in the Western world. Immune-mediated cellular damage is suspected in the pathogenesis of human HSK. The murine model has been pivotal in further establishing HSK as an immunopathological disease. This article reviews understanding of HSK, both in humans and in the mouse model, with an emphasis on possible future therapeutic strategies to counteract this blinding immunoinflammatory disease

The cellular inflammatory response in the small intestine of 21 goats infected with Schistosoma bovis was phenotypically characterized by immunohistochemistry between 6 and 32 weeks post-exposure, with particular reference to perioval granulomatous reactions. Macrophages of granulomas consistently expressed MHC class II molecules, whereas multi-nucleated giant cells in general did not. Most granulomas contained moderate infiltrates of CD2+ (CD4+ or CD8+) and γ/δ (T19+) T cells, whereas B lymphocytes were sparse. Intact extravascular mucosal eggs, lacking appreciable cellular reactivity on plain histopathology, displayed surrounding collars of MHC class II+ macrophages. Gamma/delta T cells and MHC class II+ macrophages were the predominant cell types in perivascular inflammatory cell clusters in the submucosa. The phenotypic cellular composition of granulomas did not change appreciably with duration of infection. The results indicate the importance of MHC class II-restricted immune events in the caprine S. bovis egg granulomas and also suggest a role of γ/δ T cells in their pathogenesis. It is hypothesized that the early appearance of perioval macrophage collars may serve to protect eggs from ovicidal host defence mechanisms, facilitating excretion and continuation of the life-cycle.

The relationship between cell-mediated granulomatous inflammation and transmission of disease in schistosomiasis and tuberculosis has been explored. In 2 experiments involving Schistosoma mansoni-infected normal and T cell-deprived mice, and infected deprived mice that had been variously reconstituted with immune or normal lymphocytes or immune serum, there was a significant positive numerical correlation between mean liver granuloma diameters and faecal egg counts in individual animals. Lymphocytes from donors with recently patent infections were more active than cells from chronically infected or uninfected donors in reconstituting egg excretion rates in deprived recipients, and mesenteric lymph node (MLN) cells were more active than spleen cells. Modulation of granulomatous activity with increasing chronicity of infection in the donors, resulting in a decrease in granuloma size around freshly produced tissue-bound eggs, was paralleled by a waning of the capacity of transferred lymph node cells to reconstitute egg excretion in the recipients. Serum taken from chronically infected donor mice over the same period and transferred to infected deprived recipients became more active in enhancing egg excretion in the recipients as the cell-mediated activity declined. A recent study in Kenya has found that S. mansoni-infected patients with concurrent human immunodefficiency virus (HIV) infection excrete fewer eggs than patients exposed to the same levels of schistosome infection, but who are not HIV-infected, thus indicating that schistosome egg excretion in humans is also immune-dependent. Attention is drawn to an apparently parallel situation in human tuberculosis, another pathogen which induces a cell-mediated granulomatous immune response. Several studies have shown that patients with tuberculosis who are also HIV-seropositive tend to have fewer tubercle bacilli detectable in their saliva than those with tuberculosis, but who are HIV-negative. This discrepancy, associated with differences in lung pathology in HIV-positive patients, suggests that in tuberculosis immune cell-mediated granulomatous inflammation causes the destruction of host tissue in a manner which facilitates onward transmission of the bacterial pathogen.