scholarly journals Anti-Leptospira immunoglobulin profiling in mice reveals strain specific IgG and persistent IgM responses associated with virulence and renal colonization

2021 ◽  
Vol 15 (3) ◽  
pp. e0008970
Author(s):  
Frédérique Vernel-Pauillac ◽  
Gerald L. Murray ◽  
Ben Adler ◽  
Ivo G. Boneca ◽  
Catherine Werts
Keyword(s):  
Post Infection ◽  
Severe Disease ◽  
Humoral Response ◽  
Antibody Responses ◽  
High Dose ◽  
Specific Igg ◽  
High Doses ◽  
Rats And Mice ◽  
Renal Infection

Leptospira interrogans is a pathogenic spirochete responsible for leptospirosis, a neglected, zoonotic reemerging disease. Humans are sensitive hosts and may develop severe disease. Some animal species, such as rats and mice can become asymptomatic renal carriers. More than 350 leptospiral serovars have been identified, classified on the basis of the antibody response directed against the lipopolysaccharide (LPS). Similarly to whole inactivated bacteria used as human vaccines, this response is believed to confer only short-term, serogroup-specific protection. The immune response of hosts against leptospires has not been thoroughly studied, which complicates the testing of vaccine candidates. In this work, we studied the immunoglobulin (Ig) profiles in mice infected with L. interrogans over time to determine whether this humoral response confers long-term protection after homologous challenge six months post-infection. Groups of mice were injected intraperitoneally with 2×107 leptospires of one of three pathogenic serovars (Manilae, Copenhageni or Icterohaemorrhagiae), attenuated mutants or heat-killed bacteria. Leptospira-specific immunoglobulin (IgA, IgM, IgG and 4 subclasses) produced in the first weeks up to 6 months post-infection were measured by ELISA. Strikingly, we found sustained high levels of IgM in mice infected with the pathogenic Manilae and Copenhageni strains, both colonizing the kidney. In contrast, the Icterohaemorrhagiae strain did not lead to kidney colonization, even at high dose, and triggered a classical IgM response that peaked at day 8 post-infection and disappeared. The virulent Manilae and Copenhageni serovars elicited high levels and similar profiles of IgG subclasses in contrast to Icterohaemorrhagiae strains that stimulated weaker antibody responses. Inactivated heat-killed Manilae strains elicited very low responses. However, all mice pre-injected with leptospires challenged with high doses of homologous bacteria did not develop acute leptospirosis, and all antibody responses were boosted after challenge. Furthermore, we showed that 2 months post challenge, mice pre-infected with the attenuated M895 Manilae LPS mutant or heat-killed bacterin were completely protected against renal colonization. In conclusion, we observed a sustained IgM response potentially associated with chronic leptospiral renal infection. We also demonstrated in mice different profiles of protective and cross-reactive antibodies after L. interrogans infection, depending on the serovar and virulence of strains.

scholarly journals Anti-Leptospira immunoglobulin profiling in mice reveals strain specific IgG and persistent IgM responses associated with virulence and renal colonization

2020 ◽  
Author(s):  
Frédérique Vernel-Pauillac ◽  
Gerald Murray ◽  
Ben Adler ◽  
Ivo G. Boneca ◽  
Catherine Werts
Keyword(s):  
Immune Response ◽  
Antibody Response ◽  
Post Infection ◽  
Severe Disease ◽  
Humoral Response ◽  
Antibody Responses ◽  
High Dose ◽  
Leptospira Interrogans ◽  
Homologous Challenge

AbstractLeptospira interrogans is a pathogenic spirochete responsible for leptospirosis, a neglected, zoonotic reemerging disease. Humans are sensitive hosts and may develop severe disease. Some animal species, such as rats and mice can become asymptomatic renal carriers. More than 350 leptospiral serovars have been identified, classified on the basis of the antibody response directed against the lipopolysaccharide (LPS). Similarly to whole inactivated bacteria used as human vaccines, this response is believed to confer only short-term, serogroup-specific protection. The immune response of hosts against leptospires has not been thoroughly studied and correlates of protection would be required to test vaccine candidates. In this work, we studied the immunoglobulin (Ig) profiles in mice infected with L. interrogans over time to determine whether this humoral response confers long-term protection after homologous challenge six months post-infection.Groups of mice were injected intraperitoneally with 2×107 leptospires of one of three pathogenic serovars (Manilae, Copenhageni or Icterohaemorrhagiae), attenuated mutants or heat-killed bacteria. Leptospira-specific immunoglobulin (IgA, IgM, IgG and 4 subclasses) produced in the first weeks up to 6 months post-infection were measured by ELISA. Strikingly, we found sustained high levels of IgM in mice infected with the pathogenic Manilae and Copenhageni strains, both colonizing the kidney. In contrast, the Icterohaemorrhagiae strain did not lead to kidney colonization, even at high dose, and triggered a classical IgM response that peaked at day 8 post-infection and disappeared. The virulent Manilae and Copenhageni serovars elicited high levels and similar profiles of IgG subclasses in contrast to Icterohaemorrhagiae strains that stimulated weaker antibody responses. Inactivated heat-killed Manilae strains elicited very low responses. However, all mice pre-injected with leptospires challenged with high doses of homologous bacteria did not develop acute leptospirosis, and all antibody responses were boosted after challenge. Furthermore, we showed that 2 months post challenge, mice pre-infected with the M895 Manilae LPS mutant or heat-killed bacterin were completely protected against renal colonization. In conclusion, we observed a sustained IgM response potentially associated with chronic leptospiral renal infection. We also demonstrated in mice different profiles of protective antibody response after L. interrogans infection, depending on the serovar and virulence of strains.Author summaryLeptospira interrogans is a pathogenic spirochete responsible for leptospirosis, a neglected zoonotic reemerging disease. The immune response of hosts against these bacteria has not been thoroughly studied. Here, we studied over 6 months the immunoglobulin (Ig) profiles in mice infected with L. interrogans and determined whether this humoral response confers long-term protection after homologous challenge six months after primary infection. Groups of mice were infected intraperitoneally with 2×107 bacteria of one of three different pathogenic serovars (Manilae, Copenhageni and Icterohaemorrhagiae) and some corresponding attenuated avirulent mutants. We measured by ELISA each type of Leptospira-specific Ig (IgA, IgM, IgG and 4 subclasses) produced in the first weeks up to 6 months post-infection. We showed different profiles of antibody response after L. interrogans challenge in mice, depending on the serovar and virulence of strains. However, all infected mice, including the ones harboring low antibody levels, like mice vaccinated with an inactivated, heat-killed strain, were protected against leptospirosis after challenge. Notably, we also showed an unusual sustained IgM response associated with chronic leptospiral colonization. Altogether, this long-term immune protection is different from what is known in humans and warrants further investigation.

scholarly journals Circulating IgG Levels in SARS-CoV-2 Convalescent Individuals in Cyprus

2021 ◽  
Vol 10 (24) ◽  
pp. 5882
Author(s):  
Ioannis Mamais ◽  
Apostolos Malatras ◽  
Gregory Papagregoriou ◽  
Natasa Giallourou ◽  
Andrea C. Kakouri ◽  
...  
Keyword(s):  
General Population ◽  
Humoral Response ◽  
Antibody Responses ◽  
Receptor Binding Domain ◽  
Igg Antibodies ◽  
Past Infection ◽  
Specific Igg ◽  
The University ◽  
Antibody Levels

Long-term persistence and the heterogeneity of humoral response to SARS-CoV-2 have not yet been thoroughly investigated. The aim of this work is to study the production of circulating immunoglobulin class G (IgG) antibodies against SARS-CoV-2 in individuals with past infection in Cyprus. Individuals of the general population, with or without previous SARS-CoV-2 infection, were invited to visit the Biobank at the Center of Excellence in Biobanking and Biomedical Research of the University of Cyprus. Serum IgG antibodies were measured using the SARS-CoV-2 IgG and the SARS-CoV-2 IgG II Quant assays of Abbott Laboratories. Antibody responses to SARS-CoV-2 were also evaluated against participants’ demographic and clinical data. All statistical analyses were conducted in Stata 16. The median levels of receptor binding domain (RBD)-specific IgG in 969 unvaccinated individuals, who were reportedly infected between November 2020 and September 2021, were 432.1 arbitrary units (AI)/mL (interquartile range—IQR: 182.4–1147.3). Higher antibody levels were observed in older participants, males, and those who reportedly developed symptoms or were hospitalized. The RBD-specific IgG levels peaked at three months post symptom onset and subsequently decreased up to month six, with a slower decay thereafter. IgG response to the RBD of SARS-CoV-2 is bi-phasic with considerable titer variability. Levels of IgG are significantly associated with several parameters, including age, gender, and severity of symptoms.

scholarly journals Phosphorus Inactivation in Lake Sediments Using Calcite Materials and Controlled Resuspension—Mechanism and Efficiency

Minerals ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 223
Author(s):  
Agnieszka Bańkowska-Sobczak ◽  
Aurelia Blazejczyk ◽  
Elisabeth Eiche ◽  
Uwe Fischer ◽  
Zbigniew Popek
Keyword(s):  
Adsorption Capacity ◽  
Soluble Reactive Phosphorus ◽  
High Dose ◽  
Eutrophic Lakes ◽  
Precipitated Calcium Carbonate ◽  
Anoxic Conditions ◽  
P Fraction ◽  
Reactive Phosphorus ◽  
High Doses

The efficiency and mechanism of orthophosphate—soluble reactive phosphorus (SRP)—inactivation in eutrophic lakes using controlled resuspension and calcite application into the sediment were investigated in this study. Two calcite materials, industrially produced precipitated calcium carbonate (PCC) and natural ground limestone (GCC), were tested in short-term batch experiments and long-term sediment incubations under oxic and anoxic conditions. Maximum SRP adsorption capacity calculated using Langmuir model for PCC (3.11 mg PO43− g−1) was 6 times higher than of GCC (0.43 mg PO43− g−1), reflecting substantial difference in the surface area of calcite materials (12.36 and 1.72 m2 g−1, respectively). PCC applied into the sediment during controlled resuspension reduced SRP release by 95% (oxic) and 78% (anoxic incubation) at medium dose (0.75 kg m−2) and suppressed it completely at high dose (1.5 kg m−2) for at least 3 months, irrespectively of incubation conditions. The maximum achieved reduction of SRP release using GCC was also meaningful: 78% under oxic and 56% under anoxic conditions, but this required very high doses of this material (6 kg m−2). Mechanisms of SRP inactivation by calcites were: (1) adsorption of SRP during application into the resuspended sediment and (2) precipitation of calcium-phosphate compounds (Ca-PO4) during subsequent incubation, which was reflected in a substantial increase in the HCl-P fraction (phosphorus extractable in 0.5 M HCl) in sediments enriched with calcite, irrespectively of oxygen presence. However, anoxia strongly promoted the formation of this fraction: the rise of HCl-P was 2–6 times higher in anoxic than in oxic conditions, depending on the dose and form of calcite applied. The results showed that SRP inactivation using the controlled resuspension method is only successful if highly efficient reactive materials are used, due to large amount of SRP being released from sediment during resuspension. Thus, calcite materials exhibiting high adsorption capacity should be used in this lakes’ restoration technology to ensure fast and sufficient SRP inactivation. The rise in the HCl-P fraction in sediment suggests SRP inactivation through precipitation of relatively stable Ca-PO4 minerals, which makes calcite a suitable agent for sustainable, long term SRP inactivation. As anoxic conditions promoted formation of these compounds, calcite seems to be a promising SRP inactivation agent in highly reductive sediments.

Effects of long-term continuous GnRH administration on the pituitary–gonadal axis in Eld's deer stags (Cervus eldi thamin)

1995 ◽  
Vol 73 (9) ◽  
pp. 1609-1619 ◽  
Author(s):  
S. L. Monfort ◽  
J. L. Brown ◽  
T. C. Wood ◽  
M. Bush ◽  
L. R. Williamson ◽  
...  
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
High Dose ◽  
Fertile Period ◽  
Nonbreeding Season ◽  
Testosterone Secretion ◽  
High Doses ◽  
Seasonal Decline ◽  
Seasonally Breeding

Eld's deer stags (Cervus eldi thamin) (in groups of three) were continuously administered gonadotropin-releasing hormone (GnRH) in control, low, medium, or high doses (0, 20.1 ± 0.7, 83.3 ± 2.6, and 292.9 ± 4.9 ng∙kg−1∙d−1, respectively) via osmotic minipumps for ~80 d to investigate the potential for precociously reactivating the pituitary–testicular axis during the nonbreeding season. Secretory patterns of LH, FSH, and testosterone concentrations were qualitatively similar among treatments. However, in the low-dose group, basal LH and FSH concentrations were both increased (p < 0.05) and pituitary responsiveness to a superimposed GnRH challenge was augmented (p < 0.05) after 12 weeks of treatment compared with all other groups. Despite these endocrine changes, continuous low-dose GnRH administration was not effective for precociously inducing testicular activity in this seasonally breeding species. High-dose GnRH administration initially induced a transient increase in LH, FSH, and testosterone secretion and delayed, but did not prevent, the seasonal decline in spermatogenesis. After 6–12 weeks of high-dose GnRH administration, however, attenuated pituitary responsiveness appeared to delay the normal seasonal reactivation of the pituitary–gonadal axis. In conclusion, prolonged, continuous low-dose GnRH administration did not effectively translate into a precocious onset of testicular activity; therefore, this specific approach is unlikely to be useful for prolonging the fertile period in this seasonally breeding species.

Fluconazole-Induced Symptomatic Phenytoin Toxicity

1994 ◽  
Vol 28 (2) ◽  
pp. 191-195 ◽  
Author(s):  
Richard M. Cadle ◽  
Golden J. Zenon ◽  
Maria C. Rodriguez-Barradas ◽  
Richard J. Hamill
Keyword(s):  
Continuous Monitoring ◽  
Case Reports ◽  
Review Literature ◽  
High Dose ◽  
Data Synthesis ◽  
High Doses ◽  
Phenytoin Toxicity ◽  
Cytochrome P 450 ◽  
Hepatic Cytochrome

OBJECTIVE: To report two cases of fluconazole-induced symptomatic phenytoin toxicity and review literature related to this interaction. DATA SOURCES: Case reports and review articles identified by a computerized (MEDLINE) and manual ( Index Medicus) search. DATA SYNTHESIS: Fluconazole is a broad-spectrum triazole antifungal agent primarily eliminated by renal mechanisms, although hepatic cytochrome P-450 inhibition and hepatotoxicity have been observed. We report two cases of fluconazole-induced symptomatic phenytoin toxicity. Both patients received high doses of the drug; one patient developed phenytoin toxicity only after long-term coadministration. Previously reported cases have occurred primarily with high-dose fluconazole and short-term coadministration. CONCLUSIONS: Fluconazole can increase phenytoin serum concentrations leading to toxicity. Constant and continuous monitoring of serum phenytoin concentrations with fluconazole doses as low as 200 mg/d is warranted.

scholarly journals Occurrence of COVID-19 Symptoms During SARS-CoV-2 Infection Defines Waning of Humoral Immunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Jun Wu ◽  
Bo-Yun Liang ◽  
Yao-Hui Fang ◽  
Hua Wang ◽  
Xiao-Li Yang ◽  
...  
Keyword(s):  
Humoral Immunity ◽  
Antibody Responses ◽  
Surveillance Program ◽  
Igg Antibodies ◽  
Immunization Programs ◽  
Specific Igg ◽  
Asymptomatic Infections ◽  
Asymptomatic Individuals ◽  
Specific Igg Antibodies

Approximately half of the SARS-CoV-2 infections occur without apparent symptoms, raising questions regarding long-term humoral immunity in asymptomatic individuals. Plasma levels of immunoglobulin G (IgG) and M (IgM) against the viral spike or nucleoprotein were determined for 25,091 individuals enrolled in a surveillance program in Wuhan, China. We compared 405 asymptomatic individuals who mounted a detectable antibody response with 459 symptomatic COVID-19 patients. The well-defined duration of the SARS-CoV-2 endemic in Wuhan allowed a side-by-side comparison of antibody responses following symptomatic and asymptomatic infections without subsequent antigen re-exposure. IgM responses rapidly declined in both groups. However, both the prevalence and durability of IgG responses and neutralizing capacities correlated positively with symptoms. Regardless of sex, age, and body weight, asymptomatic individuals lost their SARS-CoV-2-specific IgG antibodies more often and rapidly than symptomatic patients did. These findings have important implications for immunity and favour immunization programs including individuals after asymptomatic infections.

scholarly journals Dynamic change and clinical relevance of post-infectious SARS-CoV-2 antibody responses

2021 ◽  
Author(s):  
P W G Mallon ◽  
W Tinago ◽  
A Garcia Leon ◽  
K McCann ◽  
G Kenny ◽  
...  
Keyword(s):  
Disease Severity ◽  
Symptom Onset ◽  
Post Infection ◽  
Dynamic Change ◽  
Severe Disease ◽  
Additive Models ◽  
Antibody Responses ◽  
Rapid Decline ◽  
Relative Differences ◽  
Post Infectious

Abstract Background Although reports suggest that most individuals with COVID-19 develop detectable antibodies post infection, the kinetics, durability, and relative differences between IgM and IgG responses beyond the first few weeks after symptom onset remain poorly understood. Methods Within a large, well-phenotyped, diverse, prospective cohort of subjects with and without SARS-CoV-2 PCR-confirmed infection and historical controls derived from cohorts with high prevalence of viral coinfections and samples taken during prior flu seasons, we measured SARS-CoV-2 serological responses (both IgG and IgM) using commercially available assays. We calculated sensitivity and specificity, relationship with disease severity and mapped the kinetics of antibody responses over time using generalised additive models. Results We analysed 1,001 samples from 752 subjects, 327 with confirmed SARS-CoV-2 (29.7% with severe disease) spanning a period of 90 days from symptom onset. Sensitivity was lower (44.1-47.1%) early (&lt;10 days) after symptom onset but increased to &gt;80% after 10 days. IgM positivity increased earlier than IgG-targeted assays but positivity peaked between day 32 and 38 post onset of symptoms and declined thereafter, a dynamic that was confirmed when antibody levels were analysed, with more rapid decline observed with IgM. Early (&lt;10 days) IgM but not IgG levels were significantly higher in those who subsequently developed severe disease (signal / cut-off 4.20 (0.75-17.93) versus 1.07 (0.21-5.46), P=0.048). Conclusions This study suggests that post-infectious antibody responses in those with confirmed COVID-19 begin to decline relatively early post infection and suggests a potential role for higher IgM levels early in infection predicting subsequent disease severity

scholarly journals Early Humoral Response Correlates with Disease Severity and Outcomes in COVID-19 Patients

Viruses ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1390
Author(s):  
Anwar M. Hashem ◽  
Abdullah Algaissi ◽  
Sarah A. Almahboub ◽  
Mohamed A. Alfaleh ◽  
Turki S. Abujamel ◽  
...  
Keyword(s):  
Disease Severity ◽  
Neutralizing Antibodies ◽  
Humoral Response ◽  
Mortality Rates ◽  
Antibody Responses ◽  
High Morbidity ◽  
Clinical Presentations ◽  
Specific Igg ◽  
Almost All ◽  
Kinetics Of

The Coronavirus Disease 2019 (COVID-19), caused by SARS-CoV-2, continues to spread globally with significantly high morbidity and mortality rates. Antigen-specific responses are of unquestionable value for clinical management of COVID-19 patients. Here, we investigated the kinetics of IgM, IgG against the spike (S) and nucleoproteins (N) proteins and their neutralizing capabilities in hospitalized COVID-19 patients with different disease presentations (i.e., mild, moderate or severe), need for intensive care units (ICU) admission or outcomes (i.e., survival vs death). We show that SARS-CoV-2 specific IgG, IgM and neutralizing antibodies (nAbs) were readily detectable in almost all COVID-19 patients with various clinical presentations. Interestingly, significantly higher levels of nAbs as well as anti-S1 and -N IgG and IgM antibodies were found in patients with more severe symptoms, patients requiring admission to ICU or those with fatal outcomes. More importantly, early after symptoms onset, we found that the levels of anti-N antibodies correlated strongly with disease severity. Collectively, these findings provide new insights into the kinetics of antibody responses in COVID-19 patients with different disease severity.

Long-term treatment with finasteride induces apoptosis and pathological changes in female mice

2019 ◽  
Vol 38 (7) ◽  
pp. 762-774 ◽  
Author(s):  
AA Alkahtane ◽  
G Albasher ◽  
NK Al-Sultan ◽  
WS Alqahtani ◽  
S Alarifi ◽  
...  
Keyword(s):  
Serum Levels ◽  
Term Treatment ◽  
Androgenetic Alopecia ◽  
High Dose ◽  
Histopathological Analysis ◽  
Once Daily ◽  
Female Mice ◽  
Long Term Treatment ◽  
High Doses

Androgenetic alopecia is the most common type of alopecia, and it affects humans of both genders. Finasteride is a type II selective 5α-reductase inhibitor that is administered orally to treat androgenetic alopecia and benign prostatic hyperplasia in human males. However, its effect on the vital organs of females is unknown. This study was designed to investigate the effects of finasteride on the vital organs such as liver, kidney, and heart of female mice. To study the prospective effects of finasteride, female mice were orally administered two doses of finasteride (0.5 and 1.5 mg/kg) once daily for 35 days, and serum levels of various biochemical parameters and histopathology of various organs were examined. The results showed that serum levels of alkaline phosphatase were significantly increased by both high- and low-dose finasteride, whereas cholesterol was significantly increased by the high dose only. Creatine kinase was significantly increased by the high and low doses, whereas glucose was significantly decreased by both doses. Histopathological analysis and DNA damage assays showed that finasteride has adverse effects within both the short and the long periods in female mice. In addition, the proapoptotic genes Bax and caspase-3 were significantly increased by high dose finasteride, whereas the antiapoptotic gene Bcl-2 was significantly decreased by the low and high doses. In conclusion, finasteride is not currently approved for therapeutic use in females, and the findings in this study suggest caution in any future consideration of such use.

scholarly journals Dynamic change and clinical relevance of post-infectious SARS-CoV-2 antibody responses

2021 ◽  
Author(s):  
PWG Mallon ◽  
W Tinago ◽  
A Garcia Leon ◽  
K McCann ◽  
G Kenny ◽  
...  
Keyword(s):  
Disease Severity ◽  
Symptom Onset ◽  
Post Infection ◽  
Dynamic Change ◽  
Severe Disease ◽  
Additive Models ◽  
Antibody Responses ◽  
Rapid Decline ◽  
Relative Differences ◽  
Post Infectious

AbstractBackgroundAlthough reports suggest that most individuals with COVID-19 develop detectable antibodies post infection, the kinetics, durability, and relative differences between IgM and IgG responses beyond the first few weeks after symptom onset remain poorly understood.MethodsWithin a large, well-phenotyped, diverse, prospective cohort of subjects with and without SARS-CoV-2 PCR-confirmed infection and historical controls derived from cohorts with high prevalence of viral coinfections and samples taken during prior flu seasons, we measured SARS-CoV-2 serological responses (both IgG and IgM) using commercially available assays. We calculated sensitivity and specificity, relationship with disease severity and mapped the kinetics of antibody responses over time using generalised additive models.ResultsWe analysed 1,001 samples from 752 subjects, 327 with confirmed SARS-CoV-2 (29.7% with severe disease) spanning a period of 90 days from symptom onset. Sensitivity was lower (44.1-47.1%) early (<10 days) after symptom onset but increased to >80% after 10 days. IgM positivity increased earlier than IgG-targeted assays but positivity peaked between day 32 and 38 post onset of symptoms and declined thereafter, a dynamic that was confirmed when antibody levels were analysed, with more rapid decline observed with IgM. Early (<10 days) IgM but not IgG levels were significantly higher in those who subsequently developed severe disease (signal / cut-off 4.20 (0.75-17.93) versus 1.07 (0.21-5.46), P=0.048).ConclusionsThis study suggests that post-infectious antibody responses in those with confirmed COVID-19 begin to decline relatively early post infection and suggests a potential role for higher IgM levels early in infection predicting subsequent disease severity.

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