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Macrophages (Mφ) are innate immune cells with a variety of functional phenotypes depending on the cytokine microenvironment they reside in. Mφ exhibit distinct activation patterns that are found within a wide array of activation states ranging from the originally discovered classical pro-inflammatory (M1) to the anti-inflammatory (M2) with their multi-facades. M1 cells are induced by IFNγ + LPS, while M2 are further subdivided into M2a (IL-4), M2b (Immune Complex) and M2c (IL-10) based on their inducing stimuli. Not surprisingly, Mφ activation influences the outcome of viral infections as they produce cytokines that in turn activate cells of the adaptive immune system. Generally, activated M1 cells tend to restrict viral replication, however, influenza and HIV exploit inflammation to support their replication. Moreover, M2a polarization inhibits HIV replication at the post-integration level, while HCMV encoded hrIL-10 suppresses inflammatory reactions by facilitating M2c formation. Additionally, viruses such as LCMV and Lassa Virus directly suppress Mφ activation leading to viral chronicity. Here we review how Mφ activation affects viral infection and the strategies by which viruses manipulate Mφ polarization to benefit their own fitness. An understanding of these mechanisms is important for the development of novel immunotherapies that can sway Mφ phenotype to inhibit viral replication.

CD8+ cytotoxic T cell (CTL) responses are necessary for the lysis of virally infected cells and control of infection. CTLs are activated when their TCRs bind a major histocompatibility complex (MHC)-I/peptide complex on the surface of antigen presenting cells such as macrophages (MΦ). It is now apparent that MΦ display remarkable plasticity in response to environmental signals to polarize into classically activated M(LPS + IFN-γ) or alternatively activated M(IL-4). However, little is known about how MΦ activation status influences their antigen presentation function to CD8+ T cell in models of virus infection. Consequently, we tested how polarization of spleen-derived (Sp)-MΦ impacts direct presentation of viral antigens to influence effector and proliferative CD8+ T-cell responses. We show that M(IL-4) Sp-MΦ retain MHC-I surface expression and the ability to stimulate IFN-γ production by CTL following peptide stimulation and lymphocytic choriomeningitis virus infection to levels similar to M0 and M(LPS + IFN-γ) MΦ. However, memory CD8+ T cells cultured in the presence of M(IL-4) MΦ underwent significantly reduced proliferation and produced similar IFN-γ levels as coculturing with M0 or M(LPS + IFN-γ) cells. Thus, these results show a novel ability of polarized MΦ to regulate CD8+ T-cell proliferation and effector functions during virus infection.

Macrophages (Mϕ) are highly plastic, and can acquire a variety of functional phenotypes depending on the presence of different stimuli in their local environment. Mφ stimulated by interleukin (IL)‐4 induce an alternative activation state and function as anti‐inflammatory cells and promote tissue repair. However, there is overwhelming evidence that IL‐4 can play a role in promoting inflammation. In asthma and allergic inflammation, IL‐4 mediates proinflammatory responses that lead to tissue damage. Thus the effect of IL‐4 on the outcome of the immune responses is greatly influenced by other cofactors and cytokines present in the microenvironment. R848 (resiquimod), a TLR7/8 agonist is a novel vaccine adjuvant, triggering a strong Th1‐skewed response but its efficacy as a vaccine adjuvant shows variable results. It is not currently known whether the presence of IL‐4 can dampen or enhance immunity in response to TLR7 agonists. In the present study, we sought to investigate the impact of IL‐4‐induced Mφ polarization on the outcome of R848 stimulation. The activation marker expression and production of cytokines were measured in murine spleen‐derived Mφ. Protein expression levels of innate recognition molecules and transcription factors involved, including retinoic‐acid inducible gene I, mitochondrial antiviral signaling protein, stimulator of interferon genes (STING), and IFN regulatory factors were evaluated in activated Mφ. These play a crucial role in the control of viral replication and optimal CD8+ T cell priming. We report that sustained priming with IL‐4 alone promotes an antiviral response in Mφ, and enhances proinflammatory responses to R848 treatment. This highlights the need for better understanding of IL‐4 proinflammatory functions and its potential use as a broad‐acting antiviral in combination with R848 may be used in combination with other therapies to target the innate arm of immunity against emerging infections. [ABSTRACT FROM AUTHOR]

CD8+ cytotoxic T cell (CTL) responses are necessary for the lysis of virally infected cells and control of infection. CTLs are activated when their TCRs bind a major histocompatibility complex (MHC)-I/peptide complex on the surface of antigen presenting cells such as macrophages (MΦ). It is now apparent that MΦ display remarkable plasticity in response to environmental signals to polarize into classically activated M(LPS + IFN-γ) or alternatively activated M(IL-4). However, little is known about how MΦ activation status influences their antigen presentation function to CD8+ T cell in models of virus infection. Consequently, we tested how polarization of spleen-derived (Sp)-MΦ impacts direct presentation of viral antigens to influence effector and proliferative CD8+ T-cell responses. We show that M(IL-4) Sp-MΦ retain MHC-I surface expression and the ability to stimulate IFN-γ production by CTL following peptide stimulation and lymphocytic choriomeningitis virus infection to levels similar to M0 and M(LPS + IFN-γ) MΦ. However, memory CD8+ T cells cultured in the presence of M(IL-4) MΦ underwent significantly reduced proliferation and produced similar IFN-γ levels as coculturing with M0 or M(LPS + IFN-γ) cells. Thus, these results show a novel ability of polarized MΦ to regulate CD8+ T-cell proliferation and effector functions during virus infection. [ABSTRACT FROM AUTHOR]

Introduction. Placenta is the organ responsible for mediating the metabolic activity between mother and fetus, so it is directly involved in the normal growth of the fetus. Normal placentation is the result of a balance between proliferation, differentiation and trophoblast invasion. Materials and method. Our paperwork is based on a review of cases of placental abnormalities in the literature, with the purpose of highlighting the methods of primary ultrasound diagnosis of pregnancy. Maternal complications caused by short-term placental defects are uncontrolled bleeding, uterine apoplexy, coagulation disorders, acute renal failure, maternal death, and long-term mortality increased by cardiovascular disease. Fetal impairment starts with the restriction of intrauterine growth, prematurity and acute fetal suffering until death in utero. Defective angiogenesis or abnormalities in placental villi cause the change of blood flow, with important effects on fetal development. Results. Fetal ultrasonography is one of the main diagnostic methods in the first trimester of pregnancy, targeting both the descriptive anatomy and the modification of the utero-placental vascularization. Thus, placental function can be assessed by Doppler ultrasonography, following certain ultrasound marks, such as pulsatility index and resistance of the uterine artery, which can reveal an increased placental resistance, as well as the consequence of an incomplete transformation of a spiral artery. 3D Doppler ultrasonography is a superior diagnostic method which evaluates several aspects of the placental vascularisation. Another ultrasound marker used in the detection of placental abnormalities is the measurement of blood flow in the subplacental myometrium in the first trimester of pregnancy. A controversial method of diagnosis in the first trimester of pregnancy is fetal ultrasonography with contrast substance, which shows a real-time blood flow modified in different portions of the placenta, and also evaluates the tissular perfusion. Conclusions. Fetal ultrasound in the first trimester of pregnancy has increased specificity and sensitivity, only correlated with biological markers, in the early diagnosis of placental abnormalities [ABSTRACT FROM AUTHOR]

The placenta is the body responsible for mediating metabolic activities between mother and fetus, therefore it is directly involved in the normal development of the fetus. Normal placentation is the result of a balance between proliferation, differentiation and trophoblast invasion. Abnormal placental development has been associated with multiple gestational pathologies, such as preeclampsia, intrauterine growth restriction, diabetes and gestational trophoblastic disease. Our work is based on a review of cases of placental anomalies in the specialised literature, in order to highlight the diagnosis methods in the first trimester of pregnancy. Maternal complications caused by short-term placental defects are uncontrolled bleeding, uterine apoplexy, coagulation disorders, acute renal failure, leading to death, and on the long term, increased mortality from cardiovascular disease. Fetal impairment starts from intrauterine growth restriction, prematurity, acute fetal suffering until in utero death. Postpartum effects may be neonatal anaemia and respiratory distress syndrome. The main diagnostic method is fetal ultrasonography, dealing with both descriptive anatomy and changes of in utero placental vascularization. A defective angiogenesis or anomalies at the level of placental vilosities lead to the alteration of blood flow, with important effects on fetal development. Therefore, placental function can be evaluated through Doppler ultrasonography, following certain ultrasound markers, such as pulsatility and uterine resistance indicators, which may show increased placental resistance, as a consequence of incomplete transformation of the spiral arteries. Another ultrasound marker used for the detection of placental anomalies is blood flow measurement in the subplacental myometrium in the first trimester of pregnancy. A superior diagnosis method in the first trimester of the pregnancy is fetal ultrasonography with contrast substance, which highlights a real-time modified blood flow in different portions of the placenta, evaluating tissue perfusion. In conclusion, fetal ultrasound in the first trimester of pregnancy represents an efficient diagnostic method in placental anomalies, as well as evaluating their impact on the mother and fetal evolution, in an attempt to diagnose the associated pathologies in a timely manner and to apply a correct therapeutic management. [ABSTRACT FROM AUTHOR]