Subsequent Course Of Infection Research Articles

Intertwined Dysregulation of Ribosomal Proteins and Immune Response Delineates SARS-CoV-2 Vaccination Breakthroughs.

Globally, COVID-19 vaccines have emerged as a boon, especially during the severe pandemic phases to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, saving millions of lives. However, mixed responses to vaccination with breakthrough challenges provided a rationale to explore the immune responses generated postvaccination, which plausibly alter the subsequent course of infection. In this regard, we comprehensively profiled the nasopharyngeal transcriptomic signature of double-dose-vaccinated individuals with breakthrough infections in comparison to unvaccinated infected persons. The vaccinated individuals demonstrated a gross downregulation of ribosomal proteins along with immune response genes and transcription/translational machinery that methodically modulated the entire innate immune landscape toward immune tolerance, a feature of innate immune memory. This coordinated response was orchestrated through 17 transcription factors captured as differentially expressed in the vaccination breakthroughs, including epigenetic modulators of CHD1 and LMNB1 and several immune response effectors, with ELF1 emerging as one of the important transcriptional regulators of the antiviral innate immune response. Deconvolution algorithm using bulk gene expression data revealed decreased T-cell populations with higher expression of memory B cells in the vaccination breakthroughs. Thus, vaccination might synergize the innate immune response with humoral and T-cell correlates of protection to more rapidly clear SARS-CoV-2 infections and reduce symptoms within a shorter span of time. An important feature invariably noted after secondary vaccination is downregulation of ribosomal proteins, which might plausibly be an important factor arising from epigenetic reprogramming leading to innate immune tolerance. IMPORTANCE The development of multiple vaccines against SARS-CoV-2 infection is an unprecedented milestone achieved globally. Immunization of the mass population is a rigorous process for getting the pandemic under control, yet continuous challenges are being faced, one of them being breakthrough infections. This is the first study wherein the vaccination breakthrough cases of COVD-19 relative to unvaccinated infected individuals have been explored. In the context of vaccination, how do innate and adaptive immune responses correspond to SARS-CoV-2 infection? How do these responses culminate in a milder observable phenotype with shorter hospital stay in vaccination breakthrough cases compared with the unvaccinated? We identified a subdued transcriptional landscape in vaccination breakthroughs with decreased expression of a large set of immune and ribosomal proteins genes. We propose a module of innate immune memory, i.e., immune tolerance, which plausibly helps to explain the observed mild phenotype and fast recovery in vaccination breakthroughs.

Heterologous post-infection immunity against Egyptian avian influenza virus (AIV) H9N2 modulates the course of subsequent infection by highly pathogenic AIV H5N1, but vaccination immunity does not.

In Egypt, zoonotic A/goose/Guangdong/1/96 (gs/GD-like) highly pathogenic avian influenza virus (HPAIV) H5N1 of clade 2.2.1.2 is entrenched in poultry populations and has co-circulated with low-pathogenic avian influenza virus H9N2 of the G1 lineage since 2010. Here, the impact of H9N2 infection or vaccination on the course of consecutive infection with a lethal Egyptian HPAIV H5N1 is studied. Three-week-old chickens were infected with H9N2 or vaccinated with inactivated H9N2 or H5N1 antigens and challenged three weeks later by an HPAIV H5N1. Interestingly, pre-infection of chickens with H9N2 decreased the oral excretion of H5N1 to levels that were comparable to those of H5N1-immunized chickens, but vaccination with inactivated H9N2 did not. H9N2 pre-infection modulated but did not conceal clinical disease by HPAIV H5N1. By contrast, homologous H5 vaccination abolished clinical syndromic surveillance, although vaccinated clinical healthy birds were capable of spreading the virus.

Host detection and the stealthy phenotype in influenza virus infection.

The innate host response to influenza virus infection plays a critical role in determining the subsequent course of infection and the clinical outcome of disease. The host has a diverse array of detection and effector mechanisms that are able to recognize and initiate effective antiviral responses. In opposition, the virus utilizes a number of distinct mechanisms to evade host detection and effector activity in order to remain "stealthy" throughout its replication cycle. In this review, we describe these host and viral mechanisms, including the major pattern recognition receptor families (the TLRs, NLRs, and RLRs) in the host and the specific viral proteins such as NS1 that are key players in this interaction. Additionally, we explore nonreductive mechanisms of viral immune evasion and propose areas important for future inquiry.

Toll Like receptor 7 regulates viral loads and cytokine secretion during acute retroviral infection

Background Acute HIV infection is characterized by a high viremia accompanied by a powerful wave of pro-inflammatory cytokines that affects the subsequent course of infection and pathogenesis. Thus, understanding the mechanisms that regulate cytokine secretion and viremia is a key priority. The innate immune receptor TLR7 has been identified a retrovirus-sensing protein, and is expressed in several key immune lineages. In vitro data suggests that HIV can trigger TLR7-dependent innate immune responses, but TLR7s role in vivo is unclear. Methods To determine whether TLR7 affects viremia or cytokine secretion during acute retroviral infection, we analyzed the plasma of wild type and TLR7 deficient mice infected with the model retrovirus, Friend virus (FV). Results We identified 16 cytokines that are significantly upregulated in the plasma of wild-type mice infected with FV, the majority of which are also upregulated during HIV infection. Individual cytokines have distinct kinetic profiles and intensities, with peak levels ranging from 5dpi to 14dpi. To examine the contribution of TLR7 to this response, we compared viral loads and cytokine levels of wild-type or TLR7 deficient mice. Surprisingly, we found that majority of the pro-inflammatory cytokines exhibited exacerbated secretion in the absence of TLR7, while only an early wave of the anti-inflammatory cytokine IL-10 was attenuated. This exacerbated cytokine storm was accompanied by an elevated viremia. Significantly, IL-10 deficient mice also exhibited elevated viremia and cytokine secretion during acute infection. By contrast, TLR7deficient mice exhibit an attenuated antibody response, while anti-viral antibody levels in IL-10 deficient mice were normal. Conclusion Our results demonstrate that TLR7 negatively regulates viral loads and cytokine secretion during acute retroviral infection by promoting an early wave of IL-10, and that TLR7 regulates the development of anti-viral antibodies independently of IL-10. These results reveal that TLR7 plays multiple roles in regulating the immune response to retroviral infection.

Vaccine with herbal adjuvant—A better cocktail to combat the infection

Cross-talk between microbe and the host makes important contribution to the subsequent course of infection. Edward Jenner and Louis Pasteur—Fathers of vaccinology have wisely thought of combating an infectious bug with the same bug in a non-infectious form. Then on, vaccines have taken a great toll as a prophylactic agent to improve the quality of human life. Vaccines are successful in controlling a substantial portion of the morbidity and mortality in the developing world. Though vaccines against few diseases like small pox, polio and cholera are highly successful, the stories of failed vaccines are far more. An ideal vaccine candidate should be able to elicit the correct response, either Th1 or Th2 to combat the infection along with a strong immune memory. Use of adjuvant in the vaccine preparation is a long standing practice. Despite major advances in our understanding of vaccine adjuvants, both old and new vaccines seem likely to depend on aluminium salts. However, these adjuvants can lead to serious adverse effects [1]. Herbal immuno-modulators are paving its way as a safe alternative [2-7]. These herbal modulators can be administered along with the vaccine to elicit a faster and stronger immune response. Various herbal preparations have been shown to exert strong immuno-modulatory properties like increase in the cytokine expression [6], enhanced activation of CD4 and CD8 T cells [4-6], enhanced NK cell activity [4], etc. The failure of various vaccines can be attributed to its inability to trigger a robust immune response necessary for protection due to subsequent exposure to an infectious agent. Use of herbal immuno-modulators perhaps might be helpful in overcoming the initial lag. For, e.g., Angelica sinensus polysaccharide (ASP) increased the production of IL-2 and IFNγ, while that of IL-4 was decreased [6]. Hence, in bacterial and viral infections, which need IFNγ for its clearance, can use ASP as an adjuvant along with the vaccine. Similarly, infections which need IL-4 for its clearance should be combined with herbal modulators favoring Th2 responses, like ginseng [3]. Herbs are usually considered to be safe. However, there is no database available which can summarize the immunological profile of the various herbs or polyherbs preparation. Hence, a note of caution is a must before choosing herbal immuno-modulators as an adjuvant.

Pretreatment with feline interferon omega and the course of subsequent infection with feline herpesvirus in cats

Recombinant feline interferon omega (rFeIFN-omega), a type I IFN, may have the potential to limit virus replication and associated clinical signs when administered early on in the course of feline herpesvirus type 1 (FHV-1) infection and reactivation, respectively. The effect of rFeIFN-omega pretreatment on the course of subsequent FHV-1 infection in cats was investigated. Nine SPF cats were divided into an IFN group (n = 5) and a control-group (n = 4). The IFN group was pretreated for 2 days with 10 000 units rFeIFN-omega twice a day topically into both eyes and 20 000 units rFeIFN-omega once a day orally, whereas the control group was mock-treated. Subsequently all cats were infected with FHV-1. Samples for FHV-1 DNA detection and quantitation, virus isolation, and titration of FHV-1 antibodies were collected. Clinical and ocular signs were recorded and scored. Courses of median individual clinical and ocular scores and virus load did not differ significantly between both groups using anova for repeated measurements. Analysis (anova) of each individual ocular parameter revealed significantly high scores for epithelial keratitis (P = 0.016) in the IFN group compared to the control group. Periods of virus shedding did not differ significantly between both groups using the Wilcoxon rank sum test. Results indicated a lack of beneficial effects of rFeIFN-omega pretreatment in the course of primary FHV-1 infection in cats.

Essential Role of CCL2 in Clustering of Splenic ERTR-9+Macrophages during Infection of BALB/c Mice byListeria monocytogenes

Early interactions between pathogens and host cells are often decisive for the subsequent course of infection. Here we investigated early events during infection by Listeria monocytogenes, a ubiquitously occurring facultative intracellular microorganism that exhibits severe pathogenicity, mainly in immunocompromised individuals. We show that the inflammatory chemokine CCL2 is highly up-regulated early after Listeria infection in spleens of BALB/c mice. ERTR-9+ macrophages of the marginal zone were identified as the only infected cells and exclusive producers of CCL2 at the early time point. Consequently, clusters of different cell types were formed around infected ERTR-9+ cells. Metallophilic MOMA-1+ marginal zone macrophages were, however, excluded from the clusters and migrated into the B-cell follicles. Depletion of CCL2 during infection resulted in a different composition of cell clusters in the spleen and increased the mortality rate of treated mice. Interestingly, ERTR-9+ macrophages no longer were part of clusters in such mice but remained at their original location in the marginal zone.

Sequential development of histologic lesions and their relationship with bacterial isolation, fecal shedding, and immune responses during progressive stages of experimental infection of lambs with Mycobacterium avium subsp. paratuberculosis.

Understanding pathogenesis during progressive stages of infection by Mycobacterium avium subsp. paratuberculosis (MAP) and finding suitable methods for its diagnosis are key to the control of Johne's disease in animals. Paratuberculosis was experimentally produced in 20 crossbred lambs by oral administration of MAP to study the sequential development of lesions between 10 and 330 days postinfection and to assess commonly used diagnostic methods such as bacterial culture, lymphocyte stimulation test (LST), and enzyme-linked immunosorbent assay (ELISA) during progressive stages of infection. Histologic lesions were classified into four grades from grade 1 (least severe) to grade 4 (most severe) on the basis of location of granulomatous lesions in different regions and layers of intestines, their association with intestinal lymphoid tissues, pattern and distribution of lesions, types of cellular infiltration, and presence of acid-fast bacilli. It is evident that infection first establishes in lymphoid tissues of the small intestine, possibly at multiple sites, producing segmental lesions and from there spreads to lamina propria and local lymph nodes. Wide variability in the histologic lesions in relation to postinfection periods and initial tropism of MAP to the intestinal lymphoid tissues (Peyer's patches) suggests a differential susceptibility of young animals, possibly because of compositional phenotypic variation of Peyer's patches influencing subsequent course of infection. Histopathology was found to be a better indicator of paratuberculous infection than bacteriology in sheep. The LST (reflecting the cellular immune response) and ELISA (reflecting the humoral immune response) had overall sensitivities of 65% (11 of 17) and 42% (8 of 19), respectively, in sheep with different types of pathology but when employed together could detect about 88% of infected animals.

In vivo alterations in cytokine production following interleukin-12 (IL-12) and anti-IL-4 antibody treatment of CB6F1 mice with chronic cutaneous leishmaniasis.

CB6F1 mice exhibit intermediate resistance to infection with Leishmania major compared to their highly susceptible (BALB/c) and resistant (C57BL/6) parental strains. Unlike the C57BL/6 and BALB/c strains, which rapidly develop dominant Th1- or Th2-type responses, respectively, after infection, CB6F1 mice develop responses in which both Th1- and Th2-type cytokines are elevated through at least the first month of infection before Th1 responses become dominant as cutaneous lesions gradually heal. We have examined the effects of interleukin-12 (IL-12) and/or anti-IL-4 antibody treatment on cytokine production and the course of disease in CB6F1 mice with chronic L. major infections. When administered at 1 month of infection, IL-12 treatment led to a rapid decrease in mRNA levels for IL-4 within parasitized lesions and a moderate increase in gamma interferon (IFN-gamma) transcript levels in lymph nodes draining the site of infection. When IL-12 and anti-IL-4 antibody were administered together, they induced a marked decrease in IL-4 and transforming growth factor beta mRNA expression within lesions and a more dramatic increase in lymph node IFN-gamma transcript levels within 4 days after treatment. In comparison, similar treatment of infected BALB/c mice led to only a moderate increase in IFN-gamma transcripts but no decrease in mRNA levels for Th2-type cytokines. Treatment of CB6F1 mice with either IL-12 or anti-IL-4 antibody had no significant effect on the subsequent course of infection, whereas combined IL-12 plus anti-IL-4 treatment resulted in a decrease in lesion size and parasite numbers and a shift towards a Th1-dominant response. These results suggest that the immediate effects of cytokine or anti-cytokine therapy may be predictive of the long-term effects on the course of infection and that down-regulation of Th-2 type cytokines may be critical to the development of a Th1-dominant response.

Trypanosoma cruzi and Leishmania Spp. Human Mixed Infection

The occurrence of leishmaniasis patients carrying a double infection with Trypanosoma cruzi has been suspected but not proved. In this study, we analyzed sera of leishmaniasis patients from a region endemic for both parasites by using immunoblotting with epimastigotes and a purified antigen specific for T. cruzi (Ag 163B6). Seven of 12 patients showed a pattern of bands characteristic of chagasic patients reacting with antigens with molecular weights of 131, 125, 116, 111, 51-45, and 43 kD, and positive reactivity with Ag 163B6. Xenodiagnosis for T. cruzi was carried out in all patients; this technique has a positivity rate of 50% in chronic chagasic patients. The presence of T. cruzi trypomastigotes was shown in the blood of three, thus confirming the existence of a double infection in humans. Since the two parasites possess cross-reacting antigens, it may be assumed that previous infection with one of the parasites may affect the course of subsequent infection with the other. Nevertheless, T. cruzi infection did not prevent the appearance of typical leishmaniasis lesions. Therefore, antigenic cross-reactivity is unable to induce a sterilizing immune response against Leishmania.

Clinical course of primary HIV infection: consequences for subsequent course of infection.

To investigate the impact of the clinical course of the primary HIV infection on the subsequent course of the infection. Prospective documenting of seroconversion, follow up at six month intervals, and analysis of disease progression by life tables. 86 Men in whom seroconversion occurred within 12 months. Progression of HIV infection, defined as CD4 lymphocyte count less than 0.5 X 10(9)/l, recurrence of HIV antigenaemia, or progression to Centers for Disease Control group IV. Median follow up was 670 (range 45-1506) days. An acute illness like glandular fever occurred in 46 (53%) subjects. Three year progression rates to Centers for Disease Control group IV was 78% at three years for those who had longlasting illnesses (duration greater than or equal to 14 days) during seroconversion as compared with 10% for those who were free of symptoms or had mild illness. All six patients who developed AIDS had had longlasting primary illnesses. Three year progression rates to a CD4 lymphocyte count less than 0.5 X 10(9)/l and to recurrence of HIV antigenaemia were significantly higher for those who had longlasting primary illnesses than those who had no symptoms or mild illness (75% v 42% and 55% v 14%, respectively). The course of primary infection may determine the subsequent course of the infection.

Wild-Type Gross Leukemia Virus. II. Influence of Immunogenetic Factors on Natural Transmission and on the Consequences of Infection<xref ref-type="fn" rid="FN2">2</xref>

To determine the influence of host genotype and other factors on the transmission of wild-type Gross virus and on the subsequent course of infection, mice of various inbred, F1 hybrid, and segregating populations were tested individually for the presence of Gross soluble antigen (GSA) or Gross (G) natural antibody in the blood. GSA was invariably present in mice of strains with a high incidence of leukemia. Among the hybrid progeny of various crosses between G+ and G− strains the proportion of mice with GSA in the plasma was influenced by a) the genotype contributed by the G− parent (whether resistant or sensitive to Passage A Gross virus) and b) the direction of the cross (whether G+♀ × G−♂ or G−♀ × G+♂). Naturally occurring G antibody was most frequent in C57BL/6 mice, which are highly resistant to Passage A Gross virus, and in the progeny of hybrids with C57BL/6. G antibody was rare in C3Hf/Bi mice, a G− strain that is sensitive to Gross virus, and in C3Hf/Bi hybrids. In populations segregating for H-2 antigens, the genotype H-2k favored the occurrence of GSA, indicating immunological tolerance, and H-2b, the occurrence of G antibody, indicating lack of tolerance.

Trichinella spiralis Infections in Thiry-Vella Fistulated Rats

A basic question concerning nutritional dependence of enteric parasites is which nutrients are obtained from the host and which from exogenous food in the lumen. Chandler, Read and Nicholas (1950) proved an endogenous thiamin source for the tapeworm Hymenolepis diminuta by parenteral injection into rats of radioactive vitamin. Earlier, by nutritional studies, Chandler (1943) proposed that the same tapeworm was independent of exogenous proteins and some vitamins, obtaining these essential nutrients by absorption from host mucosa. Development of Trichinella spiralis outside the gut suggested that certain enteric factors are not necessary for maturation of infective larvae (McCoy, 1936; Mateff, 1941). Studies by Heller (1933) also supported the view that exogenous food may not be ingested during development while contact with enteric tissues is necessary for growth of larvae. Fiilleborn (1926) used the Thiry-Vella fistula to determine whether development of dog hookworm larvae (Uncinaria stenocephala) could occur in the intestinal tract without previous pulmonary migration. Twenty-one days after implantation of 900 larvae he failed to obtain hookworm eggs from fistular washings; later, however, he did observe hookworm larvae attached to the wall and found them to be undergoing morphological differentiation. Only 1/10 of the larvae implanted were recovered; he assumed that the majority had died and been digested. It was concluded that larvae in fistulas develop much farther, before they die, than they do in the lung of trachea. Goodchild (1954), and Goodchild and Boodish (1955), reintroduced the ThiryVella fistula technique for in vivo nutritional studies of parasites. An excised section of the small intestine of white rats, free of food and with blood supply intact, was sewed to the flanks to make a fistula open to the surface at the 2 ends. Parasites were implanted into this isolated gut section free of exogenous food, while the host was maintained on a full and normal diet. Hymenolepis diminuta when placed in such a fistula has lived for as long as 4 days without exogenous food. The objective of the present research was to determine whether T. spiralis larvae can establish themselves, grow, and reproduce normally when placed in fistulas totally free of exogenous food and certain digestive enzymes. This was accomplished by placing counted, artificially excysted larvae of T. spiralis in Thiry-Vella fistulas in white rats and tracing the subsequent course of infection.