On 2016 Apr 11, Gustav van Niekerk commented:

We (van Niekerk G, 2016) have recently argued that sickness associated anorexia (SAA), evolutionary conserved across both vertebrates and invertebrates, my represent a strategy for upregulating autophagic flux systemically. As an example, patients with sepsis typically decrease a number of amino acids (AA), including branched chain AAs (see table 2 in Su L, 2015). Similar, bile acids returning into circulation (bile acid reabsorption in the gut is very efficient) inhibit hepatic autophagy by binding to FRX (Lee JM, 2014). Thus, SAA likely represents an evolutionary conserved strategy to maintain elevated levels of autophagic flux during an infection.

An upregulation of autophagy during an infection may be critical for a number of reasons:

• Serum and AA starvation induces autophagy in macrophages and protects against TB infection (Gutierrez MG, 2004).

• We speculate that hepatic autophagy may play a critical role in clearing LPS and bacteria from circulation.

• Pathogens entering a cell must quickly subvert host processes to prevent being degraded by autophagy. In this regard, upregulation of autophagic flux would confront pathogens with a narrower window of opportunity to modulate the host machinery. Thus, autophagy enhances cell autonomous defence.

• Autophagy processes ribosomal components into antimicrobial peptides (Ponpuak M, 2010). Note that all nucleated cells have ribosomes and are capable of autophagy, thus suggesting that autophagy may again enhance cell-autonomous defence.

• Autophagy is also involved in the non-canonical expression of epitopes on MHC II by non-professional antigen presenting cells such as adipocytes, muscle and endothelium cells.

Autophagy may also be important in cell survival. As an example, in tissue ischemia, the release of biocidal agents from immune cells as well as the increase in misfolded proteins resulting from a febrile response may lead to the generation of toxic protein aggregates. Here, autophagy may promote cell survival by processing ‘overflow’ of damaged protein aggregates when the proteasome pathway is overwhelmed.

Collectively, these observations suggest that autophagy probably plays an important role in both pathogen clearance and in promoting host survival. It also provides a rational basis for permissive underfeeding as a form of nutritional support. We suggest that the reason why studies present mixed results on the effect of nutritional support results from the heterogeneous context and timing. As an example, a patient in recovery might benefit from aggressive nutritional support after the body switches from a catabolic towards an anabolic state. Similarly, the kind of pathogen challenge would also impact on the efficacy of nutritional support, as derailing autophagy may render cells more susceptible towards infection by certain pathogens.

On 2016 Apr 11, Gustav van Niekerk commented:

We (van Niekerk G, 2016) have recently argued that sickness associated anorexia (SAA), evolutionary conserved across both vertebrates and invertebrates, my represent a strategy for upregulating autophagic flux systemically. As an example, patients with sepsis typically decrease a number of amino acids (AA), including branched chain AAs (see table 2 in Su L, 2015). Similar, bile acids returning into circulation (bile acid reabsorption in the gut is very efficient) inhibit hepatic autophagy by binding to FRX (Lee JM, 2014). Thus, SAA likely represents an evolutionary conserved strategy to maintain elevated levels of autophagic flux during an infection.

An upregulation of autophagy during an infection may be critical for a number of reasons:

• Serum and AA starvation induces autophagy in macrophages and protects against TB infection (Gutierrez MG, 2004).

• We speculate that hepatic autophagy may play a critical role in clearing LPS and bacteria from circulation.

• Pathogens entering a cell must quickly subvert host processes to prevent being degraded by autophagy. In this regard, upregulation of autophagic flux would confront pathogens with a narrower window of opportunity to modulate the host machinery. Thus, autophagy enhances cell autonomous defence.

• Autophagy processes ribosomal components into antimicrobial peptides (Ponpuak M, 2010). Note that all nucleated cells have ribosomes and are capable of autophagy, thus suggesting that autophagy may again enhance cell-autonomous defence.

• Autophagy is also involved in the non-canonical expression of epitopes on MHC II by non-professional antigen presenting cells such as adipocytes, muscle and endothelium cells.

Autophagy may also be important in cell survival. As an example, in tissue ischemia, the release of biocidal agents from immune cells as well as the increase in misfolded proteins resulting from a febrile response may lead to the generation of toxic protein aggregates. Here, autophagy may promote cell survival by processing ‘overflow’ of damaged protein aggregates when the proteasome pathway is overwhelmed.

Collectively, these observations suggest that autophagy probably plays an important role in both pathogen clearance and in promoting host survival. It also provides a rational basis for permissive underfeeding as a form of nutritional support. We suggest that the reason why studies present mixed results on the effect of nutritional support results from the heterogeneous context and timing. As an example, a patient in recovery might benefit from aggressive nutritional support after the body switches from a catabolic towards an anabolic state. Similarly, the kind of pathogen challenge would also impact on the efficacy of nutritional support, as derailing autophagy may render cells more susceptible towards infection by certain pathogens.